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Karbanová J, Thamm K, Fargeas CA, Deniz IA, Lorico A, Corbeil D. Prominosomes - a particular class of extracellular vesicles containing prominin-1/CD133? J Nanobiotechnology 2025; 23:61. [PMID: 39881297 PMCID: PMC11776279 DOI: 10.1186/s12951-025-03102-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 01/09/2025] [Indexed: 01/31/2025] Open
Abstract
Extracellular membrane vesicles (EVs) offer promising values in various medical fields, e.g., as biomarkers in liquid biopsies or as native (or bioengineered) biological nanocarriers in tissue engineering, regenerative medicine and cancer therapy. Based on their cellular origin EVs can vary considerably in composition and diameter. Cell biological studies on mammalian prominin-1, a cholesterol-binding membrane glycoprotein, have helped to reveal new donor membranes as sources of EVs. For instance, small EVs can originate from microvilli and primary cilia, while large EVs might be produced by transient structures such as retracting cellular extremities of cancer cells during the mitotic rounding process, and the midbody at the end of cytokinesis. Here, we will highlight the various subcellular origins of prominin-1+ EVs, also called prominosomes, and the potential mechanism(s) regulating their formation. We will further discuss the molecular and cellular characteristics of prominin-1, notably those that have a direct effect on the release of prominin-1+ EVs, a process that might be directly implicated in donor cell reprogramming of stem and cancer stem cells. Prominin-1+ EVs also mediate intercellular communication during embryonic development and adult homeostasis in healthy individuals, while disseminating biological information during diseases.
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Affiliation(s)
- Jana Karbanová
- Biotechnology Center (BIOTEC) and Center for Molecular and Cellular Bioengineering, Technische Universität Dresden, Tatzberg 47-49, 01307, Dresden, Germany.
- Tissue Engineering Laboratories, Medizinische Fakultät der Technischen Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany.
- Tissue Engineering Laboratories, Biotechnology Center, Technische Universität Dresden, Tatzberg 47-49, 01307, Dresden, Germany.
| | - Kristina Thamm
- Biotechnology Center (BIOTEC) and Center for Molecular and Cellular Bioengineering, Technische Universität Dresden, Tatzberg 47-49, 01307, Dresden, Germany
- Tissue Engineering Laboratories, Medizinische Fakultät der Technischen Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany
- denovoMATRIX GmbH, Tatzberg 47, 01307, Dresden, Germany
| | - Christine A Fargeas
- Biotechnology Center (BIOTEC) and Center for Molecular and Cellular Bioengineering, Technische Universität Dresden, Tatzberg 47-49, 01307, Dresden, Germany
- Tissue Engineering Laboratories, Medizinische Fakultät der Technischen Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany
| | - Ilker A Deniz
- Biotechnology Center (BIOTEC) and Center for Molecular and Cellular Bioengineering, Technische Universität Dresden, Tatzberg 47-49, 01307, Dresden, Germany
- Tissue Engineering Laboratories, Medizinische Fakultät der Technischen Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany
| | - Aurelio Lorico
- College of Osteopathic Medicine, Touro University Nevada, 874 American Pacific Drive, Henderson, NV, 89014, USA
| | - Denis Corbeil
- Biotechnology Center (BIOTEC) and Center for Molecular and Cellular Bioengineering, Technische Universität Dresden, Tatzberg 47-49, 01307, Dresden, Germany.
- Tissue Engineering Laboratories, Medizinische Fakultät der Technischen Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany.
- Tissue Engineering Laboratories, Biotechnology Center, Technische Universität Dresden, Tatzberg 47-49, 01307, Dresden, Germany.
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Shanmugam I, Radhakrishnan S, Santosh S, Ramnath A, Anil M, Devarajan Y, Maheswaran S, Narayanan V, Pitchaimani A. Emerging role and translational potential of small extracellular vesicles in neuroscience. Life Sci 2024; 355:122987. [PMID: 39151884 DOI: 10.1016/j.lfs.2024.122987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 08/08/2024] [Accepted: 08/13/2024] [Indexed: 08/19/2024]
Abstract
Small extracellular vesicles (sEV) are endogenous lipid-bound membrane vesicles secreted by both prokaryotic and eukaryotic cells into the extracellular environment, performs several biological functions such as cell-cell communication, transfer of proteins, mRNA, and ncRNA to target cells in distant sites. Due to their role in molecular pathogenesis and its potential to deliver biological cargo to target cells, it has become a prominent area of interest in recent research in the field of Neuroscience. However, their role in neurological disorders, like neurodegenerative diseases is more complex and still unaddressed. Thus, this review focuses on the role of sEV in neurodegenerative and neurodevelopmental diseases, including their biogenesis, classification, and pathogenesis, with translational advantages and limitations in the area of neurobiology.
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Affiliation(s)
- Iswarya Shanmugam
- Precision Nanomedicine and Microfluidic Lab, Centre for Biomaterials, Cellular and Molecular Theranostics (CBCMT), Vellore Institute of Technology, Vellore. TN, India; School of Biosciences and Technology, Vellore Institute of Technology, Vellore Campus, Tiruvalam Rd, Katpadi, Vellore, Tamil Nadu 632014, India
| | - Sivani Radhakrishnan
- School of Biosciences and Technology, Vellore Institute of Technology, Vellore Campus, Tiruvalam Rd, Katpadi, Vellore, Tamil Nadu 632014, India
| | - Shradha Santosh
- School of Biosciences and Technology, Vellore Institute of Technology, Vellore Campus, Tiruvalam Rd, Katpadi, Vellore, Tamil Nadu 632014, India
| | - Akansha Ramnath
- School of Biosciences and Technology, Vellore Institute of Technology, Vellore Campus, Tiruvalam Rd, Katpadi, Vellore, Tamil Nadu 632014, India
| | - Meghna Anil
- School of Biosciences and Technology, Vellore Institute of Technology, Vellore Campus, Tiruvalam Rd, Katpadi, Vellore, Tamil Nadu 632014, India
| | - Yogesh Devarajan
- Precision Nanomedicine and Microfluidic Lab, Centre for Biomaterials, Cellular and Molecular Theranostics (CBCMT), Vellore Institute of Technology, Vellore. TN, India; School of Biosciences and Technology, Vellore Institute of Technology, Vellore Campus, Tiruvalam Rd, Katpadi, Vellore, Tamil Nadu 632014, India
| | - Saravanakumar Maheswaran
- Precision Nanomedicine and Microfluidic Lab, Centre for Biomaterials, Cellular and Molecular Theranostics (CBCMT), Vellore Institute of Technology, Vellore. TN, India; School of Biosciences and Technology, Vellore Institute of Technology, Vellore Campus, Tiruvalam Rd, Katpadi, Vellore, Tamil Nadu 632014, India
| | - Vaibav Narayanan
- Precision Nanomedicine and Microfluidic Lab, Centre for Biomaterials, Cellular and Molecular Theranostics (CBCMT), Vellore Institute of Technology, Vellore. TN, India; School of Biosciences and Technology, Vellore Institute of Technology, Vellore Campus, Tiruvalam Rd, Katpadi, Vellore, Tamil Nadu 632014, India
| | - Arunkumar Pitchaimani
- Precision Nanomedicine and Microfluidic Lab, Centre for Biomaterials, Cellular and Molecular Theranostics (CBCMT), Vellore Institute of Technology, Vellore. TN, India; School of Biosciences and Technology, Vellore Institute of Technology, Vellore Campus, Tiruvalam Rd, Katpadi, Vellore, Tamil Nadu 632014, India.
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3
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Hu HT, Nishimura T, Kawana H, Dante RAS, D’Angelo G, Suetsugu S. The cellular protrusions for inter-cellular material transfer: similarities between filopodia, cytonemes, tunneling nanotubes, viruses, and extracellular vesicles. Front Cell Dev Biol 2024; 12:1422227. [PMID: 39035026 PMCID: PMC11257967 DOI: 10.3389/fcell.2024.1422227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Accepted: 06/17/2024] [Indexed: 07/23/2024] Open
Abstract
Extracellular vesicles (EVs) are crucial for transferring bioactive materials between cells and play vital roles in both health and diseases. Cellular protrusions, including filopodia and microvilli, are generated by the bending of the plasma membrane and are considered to be rigid structures facilitating various cellular functions, such as cell migration, adhesion, and environment sensing. Compelling evidence suggests that these protrusions are dynamic and flexible structures that can serve as sources of a new class of EVs, highlighting the unique role they play in intercellular material transfer. Cytonemes are specialized filopodia protrusions that make direct contact with neighboring cells, mediating the transfer of bioactive materials between cells through their tips. In some cases, these tips fuse with the plasma membrane of neighboring cells, creating tunneling nanotubes that directly connect the cytosols of the adjacent cells. Additionally, virus particles can be released from infected cells through small bud-like of plasma membrane protrusions. These different types of protrusions, which can transfer bioactive materials, share common protein components, including I-BAR domain-containing proteins, actin cytoskeleton, and their regulatory proteins. The dynamic and flexible nature of these protrusions highlights their importance in cellular communication and material transfer within the body, including development, cancer progression, and other diseases.
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Affiliation(s)
- Hooi Ting Hu
- Division of Biological Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Nara, Japan
| | - Tamako Nishimura
- Division of Biological Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Nara, Japan
| | - Hiroki Kawana
- Division of Biological Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Nara, Japan
| | - Rachelle Anne So Dante
- Division of Biological Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Nara, Japan
| | - Gisela D’Angelo
- Institut Curie, PSL Research University, Centre national de la recherche scientifique (CNRS), Paris, France
| | - Shiro Suetsugu
- Division of Biological Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Nara, Japan
- Data Science Center, Nara Institute of Science and Technology, Nara, Japan
- Center for Digital Green-innovation, Nara Institute of Science and Technology, Nara, Japan
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Gisina A, Yarygin K, Lupatov A. The Impact of Glycosylation on the Functional Activity of CD133 and the Accuracy of Its Immunodetection. BIOLOGY 2024; 13:449. [PMID: 38927329 PMCID: PMC11200695 DOI: 10.3390/biology13060449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Revised: 06/01/2024] [Accepted: 06/09/2024] [Indexed: 06/28/2024]
Abstract
The membrane glycoprotein CD133 (prominin-1) is widely regarded as the main molecular marker of cancer stem cells, which are the most malignant cell subpopulation within the tumor, responsible for tumor growth and metastasis. For this reason, CD133 is considered a promising prognostic biomarker and molecular target for antitumor therapy. Under normal conditions, CD133 is present on the cell membrane in glycosylated form. However, in malignancies, altered glycosylation apparently leads to changes in the functional activity of CD133 and the availability of some of its epitopes for antibodies. This review focuses on CD133's glycosylation in human cells and its impact on the function of this glycoprotein. The association of CD133 with proliferation, differentiation, apoptosis, autophagy, epithelial-mesenchymal transition, the organization of plasma membrane protrusions and extracellular trafficking is discussed. In this review, particular attention is paid to the influence of CD133's glycosylation on its immunodetection. A list of commercially available and custom antibodies with their characteristics is provided. The available data indicate that the development of CD133-based biomedical technologies should include an assessment of CD133's glycosylation in each tumor type.
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Affiliation(s)
- Alisa Gisina
- Laboratory of Cell Biology, V. N. Orekhovich Institute of Biomedical Chemistry, 119121 Moscow, Russia
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Szyposzynska A, Bielawska-Pohl A, Paprocka M, Bar J, Murawski M, Klimczak A. Comparative Analysis of Primary Ovarian Cancer Cells and Established Cell Lines as a New Tool for Studies on Ovarian Cancer Cell Complexity. Int J Mol Sci 2024; 25:5384. [PMID: 38791431 PMCID: PMC11121816 DOI: 10.3390/ijms25105384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 05/10/2024] [Accepted: 05/13/2024] [Indexed: 05/26/2024] Open
Abstract
Primary cancer cells reflect the genetic background and phenotype of a tumor. Immortalized cells with higher proliferation activity have an advantage over primary cells. The aim of the study was to immortalize the primary ovarian cancer (OvCa) cells using the plasmid-carrying human telomerase reverse transcriptase (hTERT) gene and compare their phenotype and biological activity with the primary cells. The primary OvCa3 A and OvCa7 A cells were isolated from the ascitic fluid of two high-grade serous ovarian cancer patients and were characterized using immunocytochemical methods, flow cytometry, real-time RT-PCR, Western blot, metabolic activity, and migratory potential. Both immortalized ovarian cancer cell lines mirrored the phenotype of primary cancer cells, albeit with modifications. The OvCa3 A hTERT cells kept the mesenchymal stem cell phenotype of CD73/CD90/CD105-positivity and were CD133-negative, whereas the cell population of OvCa7 A hTERT lost CD73 expression, but almost 90% of cells expressed the CD133 characteristic for the CSCs phenotype. Immortalized OvCa cells differed in gene expression level with respect to Sox2 and Oct4, which was associated with stemness properties. The OvCa7 A hTERT cells showed higher metabolic and migratory activity and ALDH1 expression than the corresponding primary OvCa cells. Both primary and immortalized cell lines were able to form spheroids. The newly established unique immortalized cell line OvCa7 A hTERT, with the characteristic of a serous ovarian cancer malignancy feature, and with the accumulation of the p53, Pax8, and overexpression of the CD133 and CD44 molecules, may be a useful tool for research on therapeutic approaches, especially those targeting CSCs in ovarian cancer and in preclinical 2D and 3D models.
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Affiliation(s)
- Agnieszka Szyposzynska
- Laboratory of Biology of Stem and Neoplastic Cells, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland; (A.S.); (A.B.-P.)
| | - Aleksandra Bielawska-Pohl
- Laboratory of Biology of Stem and Neoplastic Cells, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland; (A.S.); (A.B.-P.)
| | - Maria Paprocka
- Laboratory of Biology of Stem and Neoplastic Cells, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland; (A.S.); (A.B.-P.)
| | - Julia Bar
- Department of Immunopathology and Molecular Biology, Wroclaw Medical University, 50-556 Wroclaw, Poland;
| | - Marek Murawski
- 1st Department of Gynecology and Obstetrics, Wroclaw Medical University, 50-599 Wroclaw, Poland;
| | - Aleksandra Klimczak
- Laboratory of Biology of Stem and Neoplastic Cells, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland; (A.S.); (A.B.-P.)
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Pleskač P, Fargeas CA, Veselska R, Corbeil D, Skoda J. Emerging roles of prominin-1 (CD133) in the dynamics of plasma membrane architecture and cell signaling pathways in health and disease. Cell Mol Biol Lett 2024; 29:41. [PMID: 38532366 DOI: 10.1186/s11658-024-00554-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Accepted: 02/22/2024] [Indexed: 03/28/2024] Open
Abstract
Prominin-1 (CD133) is a cholesterol-binding membrane glycoprotein selectively associated with highly curved and prominent membrane structures. It is widely recognized as an antigenic marker of stem cells and cancer stem cells and is frequently used to isolate them from biological and clinical samples. Recent progress in understanding various aspects of CD133 biology in different cell types has revealed the involvement of CD133 in the architecture and dynamics of plasma membrane protrusions, such as microvilli and cilia, including the release of extracellular vesicles, as well as in various signaling pathways, which may be regulated in part by posttranslational modifications of CD133 and its interactions with a variety of proteins and lipids. Hence, CD133 appears to be a master regulator of cell signaling as its engagement in PI3K/Akt, Src-FAK, Wnt/β-catenin, TGF-β/Smad and MAPK/ERK pathways may explain its broad action in many cellular processes, including cell proliferation, differentiation, and migration or intercellular communication. Here, we summarize early studies on CD133, as they are essential to grasp its novel features, and describe recent evidence demonstrating that this unique molecule is involved in membrane dynamics and molecular signaling that affects various facets of tissue homeostasis and cancer development. We hope this review will provide an informative resource for future efforts to elucidate the details of CD133's molecular function in health and disease.
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Affiliation(s)
- Petr Pleskač
- Laboratory of Tumor Biology, Department of Experimental Biology, Faculty of Science, Masaryk University, Kamenice 5, 625 00, Brno, Czech Republic
- International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic
| | - Christine A Fargeas
- Biotechnology Center (BIOTEC) and Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden, Tatzberg 47/49, 01307, Dresden, Germany
- Tissue Engineering Laboratories, Medizinische Fakultät der Technischen Universität Dresden, Dresden, Germany
| | - Renata Veselska
- Laboratory of Tumor Biology, Department of Experimental Biology, Faculty of Science, Masaryk University, Kamenice 5, 625 00, Brno, Czech Republic
- International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic
| | - Denis Corbeil
- Biotechnology Center (BIOTEC) and Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden, Tatzberg 47/49, 01307, Dresden, Germany.
- Tissue Engineering Laboratories, Medizinische Fakultät der Technischen Universität Dresden, Dresden, Germany.
| | - Jan Skoda
- Laboratory of Tumor Biology, Department of Experimental Biology, Faculty of Science, Masaryk University, Kamenice 5, 625 00, Brno, Czech Republic.
- International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic.
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Karbanová J, Deniz IA, Wilsch-Bräuninger M, de Sousa Couto RA, Fargeas CA, Santos MF, Lorico A, Corbeil D. Extracellular lipidosomes containing lipid droplets and mitochondria are released during melanoma cell division. Cell Commun Signal 2024; 22:57. [PMID: 38243233 PMCID: PMC10799373 DOI: 10.1186/s12964-024-01471-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Accepted: 01/03/2024] [Indexed: 01/21/2024] Open
Abstract
BACKGROUND The incidence of melanoma is increasing worldwide. Since metastatic melanoma is highly aggressive, it is important to decipher all the biological aspects of melanoma cells. In this context, we have previously shown that metastatic FEMX-I melanoma cells release small (< 150 nm) extracellular vesicles (EVs) known as exosomes and ectosomes containing the stem (and cancer stem) cell antigenic marker CD133. EVs play an important role in intercellular communication, which could have a micro-environmental impact on surrounding tissues. RESULTS We report here a new type of large CD133+ EVs released by FEMX-I cells. Their sizes range from 2 to 6 µm and they contain lipid droplets and mitochondria. Real-time video microscopy revealed that these EVs originate from the lipid droplet-enriched cell extremities that did not completely retract during the cell division process. Once released, they can be taken up by other cells. Silencing CD133 significantly affected the cellular distribution of lipid droplets, with a re-localization around the nuclear compartment. As a result, the formation of large EVs containing lipid droplets was severely compromised. CONCLUSION Given the biochemical effect of lipid droplets and mitochondria and/or their complexes on cell metabolism, the release and uptake of these new large CD133+ EVs from dividing aggressive melanoma cells can influence both donor and recipient cells, and therefore impact melanoma growth and dissemination.
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Affiliation(s)
- Jana Karbanová
- Biotechnology Center (BIOTEC) and Center for Molecular and Cellular Bioengineering, Technische Universität Dresden, Tatzberg 47-49, Dresden, 01307, Germany
- Tissue Engineering Laboratories, Medizinische Fakultät der Technischen Universität Dresden, Fetscherstr. 74, Dresden, 01307, Germany
| | - Ilker A Deniz
- Biotechnology Center (BIOTEC) and Center for Molecular and Cellular Bioengineering, Technische Universität Dresden, Tatzberg 47-49, Dresden, 01307, Germany
- Tissue Engineering Laboratories, Medizinische Fakultät der Technischen Universität Dresden, Fetscherstr. 74, Dresden, 01307, Germany
| | - Michaela Wilsch-Bräuninger
- Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, Dresden, 01307, Germany
| | - Rita Alexandra de Sousa Couto
- Biotechnology Center (BIOTEC) and Center for Molecular and Cellular Bioengineering, Technische Universität Dresden, Tatzberg 47-49, Dresden, 01307, Germany
- Escola Superior de Biotecnologia, Universidade Católica Portuguesa, Rua de Diogo Botelho 1327, Porto, 4169-005, Portugal
| | - Christine A Fargeas
- Biotechnology Center (BIOTEC) and Center for Molecular and Cellular Bioengineering, Technische Universität Dresden, Tatzberg 47-49, Dresden, 01307, Germany
- Tissue Engineering Laboratories, Medizinische Fakultät der Technischen Universität Dresden, Fetscherstr. 74, Dresden, 01307, Germany
| | - Mark F Santos
- College of Osteopathic Medicine, Touro University Nevada, 874 American Pacific Drive, Henderson, NV, 89014, USA
| | - Aurelio Lorico
- College of Osteopathic Medicine, Touro University Nevada, 874 American Pacific Drive, Henderson, NV, 89014, USA.
| | - Denis Corbeil
- Biotechnology Center (BIOTEC) and Center for Molecular and Cellular Bioengineering, Technische Universität Dresden, Tatzberg 47-49, Dresden, 01307, Germany.
- Tissue Engineering Laboratories, Medizinische Fakultät der Technischen Universität Dresden, Fetscherstr. 74, Dresden, 01307, Germany.
- Tissue Engineering Laboratories, Biotechnology Center, Technische Universität Dresden, Tatzberg 47-49, Dresden, 01307, Germany.
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Gisina A, Kim Y, Yarygin K, Lupatov A. Can CD133 Be Regarded as a Prognostic Biomarker in Oncology: Pros and Cons. Int J Mol Sci 2023; 24:17398. [PMID: 38139228 PMCID: PMC10744290 DOI: 10.3390/ijms242417398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 12/07/2023] [Accepted: 12/11/2023] [Indexed: 12/24/2023] Open
Abstract
The CD133 cell membrane glycoprotein, also termed prominin-1, is expressed on some of the tumor cells of both solid and blood malignancies. The CD133-positive tumor cells were shown to exhibit higher proliferative activity, greater chemo- and radioresistance, and enhanced tumorigenicity compared to their CD133-negative counterparts. For this reason, CD133 is regarded as a potential prognostic biomarker in oncology. The CD133-positive cells are related to the cancer stem cell subpopulation in many types of cancer. Recent studies demonstrated the involvement of CD133 in the regulation of proliferation, autophagy, and apoptosis in cancer cells. There is also evidence of its participation in the epithelial-mesenchymal transition associated with tumor progression. For a number of malignant tumor types, high CD133 expression is associated with poor prognosis, and the prognostic significance of CD133 has been confirmed in a number of meta-analyses. However, some published papers suggest that CD133 has no prognostic significance or even demonstrate a certain correlation between high CD133 levels and a positive prognosis. This review summarizes and discusses the existing evidence for and against the prognostic significance of CD133 in cancer. We also consider possible reasons for conflicting findings from the studies of the clinical significance of CD133.
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Affiliation(s)
- Alisa Gisina
- Laboratory of Cell Biology, V. N. Orekhovich Institute of Biomedical Chemistry, 119121 Moscow, Russia
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Mayer C, Nehring S, Kücken M, Repnik U, Seifert S, Sljukic A, Delpierre J, Morales‐Navarrete H, Hinz S, Brosch M, Chung B, Karlsen T, Huch M, Kalaidzidis Y, Brusch L, Hampe J, Schafmayer C, Zerial M. Apical bulkheads accumulate as adaptive response to impaired bile flow in liver disease. EMBO Rep 2023; 24:e57181. [PMID: 37522754 PMCID: PMC10481669 DOI: 10.15252/embr.202357181] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 07/11/2023] [Accepted: 07/13/2023] [Indexed: 08/01/2023] Open
Abstract
Hepatocytes form bile canaliculi that dynamically respond to the signalling activity of bile acids and bile flow. Little is known about their responses to intraluminal pressure. During embryonic development, hepatocytes assemble apical bulkheads that increase the canalicular resistance to intraluminal pressure. Here, we investigate whether they also protect bile canaliculi against elevated pressure upon impaired bile flow in adult liver. Apical bulkheads accumulate upon bile flow obstruction in mouse models and patients with primary sclerosing cholangitis (PSC). Their loss under these conditions leads to abnormally dilated canaliculi, resembling liver cell rosettes described in other hepatic diseases. 3D reconstruction reveals that these structures are sections of cysts and tubes formed by hepatocytes. Mathematical modelling establishes that they positively correlate with canalicular pressure and occur in early PSC stages. Using primary hepatocytes and 3D organoids, we demonstrate that excessive canalicular pressure causes the loss of apical bulkheads and formation of rosettes. Our results suggest that apical bulkheads are a protective mechanism of hepatocytes against impaired bile flow, highlighting the role of canalicular pressure in liver diseases.
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Affiliation(s)
- Carlotta Mayer
- Max Planck Institute of Molecular Cell Biology and GeneticsDresdenGermany
| | - Sophie Nehring
- Department of Medicine I, Gastroenterology and HepatologyUniversity Hospital Carl‐Gustav‐Carus, Technische Universität Dresden (TU Dresden)DresdenGermany
| | - Michael Kücken
- Center for Information Services and High‐Performance ComputingTechnische Universität DresdenDresdenGermany
| | - Urska Repnik
- Central Microscopy, Department of BiologyChristian‐Albrechts‐Universtät zu Kiel (CAU)KielGermany
| | - Sarah Seifert
- Max Planck Institute of Molecular Cell Biology and GeneticsDresdenGermany
| | - Aleksandra Sljukic
- Max Planck Institute of Molecular Cell Biology and GeneticsDresdenGermany
| | - Julien Delpierre
- Max Planck Institute of Molecular Cell Biology and GeneticsDresdenGermany
| | | | - Sebastian Hinz
- Department of General SurgeryUniversity Hospital RostockRostockGermany
| | - Mario Brosch
- Department of Medicine I, Gastroenterology and HepatologyUniversity Hospital Carl‐Gustav‐Carus, Technische Universität Dresden (TU Dresden)DresdenGermany
- Center for Regenerative Therapies Dresden (CRTD)Technische Universität Dresden (TU Dresden)DresdenGermany
| | - Brian Chung
- Department of Transplantation Medicine, Clinic of Surgery, Inflammatory Medicine and Transplantation, Norwegian PSC Research CenterOslo University Hospital RikshospitaletOsloNorway
- Research Institute of Internal Medicine, Clinic of Surgery, Inflammatory Diseases and TransplantationOslo University Hospital and University of OsloOsloNorway
| | - Tom Karlsen
- Department of Transplantation Medicine, Clinic of Surgery, Inflammatory Medicine and Transplantation, Norwegian PSC Research CenterOslo University Hospital RikshospitaletOsloNorway
- Research Institute of Internal Medicine, Clinic of Surgery, Inflammatory Diseases and TransplantationOslo University Hospital and University of OsloOsloNorway
| | - Meritxell Huch
- Max Planck Institute of Molecular Cell Biology and GeneticsDresdenGermany
| | - Yannis Kalaidzidis
- Max Planck Institute of Molecular Cell Biology and GeneticsDresdenGermany
| | - Lutz Brusch
- Center for Information Services and High‐Performance ComputingTechnische Universität DresdenDresdenGermany
| | - Jochen Hampe
- Department of Medicine I, Gastroenterology and HepatologyUniversity Hospital Carl‐Gustav‐Carus, Technische Universität Dresden (TU Dresden)DresdenGermany
- Center for Regenerative Therapies Dresden (CRTD)Technische Universität Dresden (TU Dresden)DresdenGermany
| | | | - Marino Zerial
- Max Planck Institute of Molecular Cell Biology and GeneticsDresdenGermany
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Vats A, Ho TC, Puc I, Chang CH, Perng GC, Chen PL. The CD133 and CD34 cell types in human umbilical cord blood have the capacity to produce infectious dengue virus particles. Sci Rep 2023; 13:10513. [PMID: 37386042 PMCID: PMC10310799 DOI: 10.1038/s41598-023-37707-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 06/26/2023] [Indexed: 07/01/2023] Open
Abstract
Although dengue virus (DENV) can establish infections in hematopoietic stem progenitor cells (HSPCs), there is little information on dengue virus persistent infection in CD34+ and CD133+ cell surface glycoproteins of hematopoietic stem cells (HSCs). CD34 and CD133 also function as cell-cell adhesion factors, which are present in umbilical cord blood (UCB). In this study, we sought to establish a persistent infection model of DENV infection in UCB using a prolonged period of infection lasting 30 days. Post-infection, the results exhibited a productive and non-productive phase of DENV production. Using a plaque assay, Western blot, and confocal microscopy, we demonstrated that CD133 and CD34 cells are target cells for DENV infection. Moreover, we showed that DENV particles can be recovered from the non-productive phase of DENV-infected CD34 and CD133 cells after co-incubation with Vero cells. We concluded that CD133 and CD34 retain their capacity to produce the infectious virus due to proliferation and their ability to repopulate, as deduced from a BrdU proliferation assay and flow cytometry analysis using t-distributed stochastic neighbor embedding. In summary, the platform to co-culture infected primitive HSCs from their non-productive phase onto Vero cells will give new insights into understanding the DENV dynamics in cell-to-cell transmission and reactivation of the virus.
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Affiliation(s)
- Amrita Vats
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 701401, Taiwan
| | - Tzu-Chuan Ho
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 701401, Taiwan
| | - Irwin Puc
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 701401, Taiwan
| | - Chiung-Hsin Chang
- Department of Obstetrics and Gynecology, College of Medicine, National Cheng Kung University, Tainan, 701401, Taiwan
| | - Guey-Chuen Perng
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 701401, Taiwan
- Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, 701401, Taiwan
| | - Po-Lin Chen
- Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, 70428, Taiwan.
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11
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Kaida T, Fujiyama Y, Soeno T, Yokota M, Nakamoto S, Goto T, Watanabe A, Okuno K, Nie Y, Fujino S, Yokota K, Harada H, Tanaka Y, Tanaka T, Yokoi K, Kojo K, Miura H, Yamanashi T, Sato T, Sasaki J, Sangai T, Hiki N, Kumamoto Y, Naitoh T, Yamashita K. Less demand on stem cell marker-positive cancer cells may characterize metastasis of colon cancer. PLoS One 2023; 18:e0277395. [PMID: 37098074 PMCID: PMC10128954 DOI: 10.1371/journal.pone.0277395] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Accepted: 10/26/2022] [Indexed: 04/26/2023] Open
Abstract
BACKGROUND CD44 and CD133 are stem cell markers in colorectal cancer (CRC). CD44 has distinctive isoforms with different oncological properties like total CD44 (CD44T) and variant CD44 (CD44V). Clinical significance of such markers remains elusive. METHODS Sixty colon cancer were examined for CD44T/CD44V and CD133 at mRNA level in a quantitative PCR, and clarified for their association with clinicopathological factors. RESULTS (1) Both CD44T and CD44V showed higher expression in primary colon tumors than in non-cancerous mucosas (p<0.0001), while CD133 was expressed even in non-cancerous mucosa and rather decreased in the tumors (p = 0.048). (2) CD44V expression was significantly associated with CD44T expression (R = 0.62, p<0.0001), while they were not correlated to CD133 at all in the primary tumors. (3) CD44V/CD44T expressions were significantly higher in right colon cancer than in left colon cancer (p = 0.035/p = 0.012, respectively), while CD133 expression were not (p = 0.20). (4) In primary tumors, unexpectedly, CD44V/CD44T/CD133 mRNA expressions were not correlated with aggressive phenotypes, but CD44V/CD44T rather significantly with less aggressive lymph node metastasis/distant metastasis (p = 0.040/p = 0.039, respectively). Moreover, both CD44V and CD133 expressions were significantly decreased in liver metastasis as compared to primary tumors (p = 0.0005 and p = 0.0006, respectively). CONCLUSION Our transcript expression analysis of cancer stem cell markers did not conclude that their expression could represent aggressive phenotypes of primary and metastatic tumors, and rather represented less demand on stem cell marker-positive cancer cells.
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Affiliation(s)
- Takeshi Kaida
- Department of Surgery, Kitasato University Graduate School of Medical Sciences, Sagamihara, Kanagawa, Japan
- Department of Lower Gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Yoshiki Fujiyama
- Department of Surgery, Kitasato University Graduate School of Medical Sciences, Sagamihara, Kanagawa, Japan
- Department of General Pediatric and Hepatobiliary Pancreatic Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Takafumi Soeno
- Department of Surgery, Kitasato University Graduate School of Medical Sciences, Sagamihara, Kanagawa, Japan
- Department of Upper Gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Mitsuo Yokota
- Department of Surgery, Kitasato University Graduate School of Medical Sciences, Sagamihara, Kanagawa, Japan
- Department of Breast and Thyroid Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Shuji Nakamoto
- Department of General Pediatric and Hepatobiliary Pancreatic Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Takuya Goto
- Department of Surgery, Kitasato University Graduate School of Medical Sciences, Sagamihara, Kanagawa, Japan
- Department of Lower Gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Akiko Watanabe
- Department of Surgery, Kitasato University Graduate School of Medical Sciences, Sagamihara, Kanagawa, Japan
- Department of Lower Gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Kota Okuno
- Department of Surgery, Kitasato University Graduate School of Medical Sciences, Sagamihara, Kanagawa, Japan
- Department of Upper Gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Yusuke Nie
- Department of Surgery, Kitasato University Graduate School of Medical Sciences, Sagamihara, Kanagawa, Japan
- Department of General Pediatric and Hepatobiliary Pancreatic Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Shiori Fujino
- Department of Surgery, Kitasato University Graduate School of Medical Sciences, Sagamihara, Kanagawa, Japan
- Department of Breast and Thyroid Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Kazuko Yokota
- Department of Lower Gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Hiroki Harada
- Department of Upper Gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Yoko Tanaka
- Department of Breast and Thyroid Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Toshimichi Tanaka
- Department of Lower Gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Keigo Yokoi
- Department of Lower Gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Ken Kojo
- Department of Lower Gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Hirohisa Miura
- Department of Lower Gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Takahiro Yamanashi
- Department of Lower Gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Takeo Sato
- Department of Lower Gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Jiichiro Sasaki
- Multidisciplinary Cancer Care and Treatment Center, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Takafumi Sangai
- Department of Breast and Thyroid Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Naoki Hiki
- Department of Upper Gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Yusuke Kumamoto
- Department of General Pediatric and Hepatobiliary Pancreatic Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Takeshi Naitoh
- Department of Lower Gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Keishi Yamashita
- Department of Upper Gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
- Division of Advanced Surgical Oncology, Research and Development Center for New Frontiers, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
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12
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Central role of Prominin-1 in lipid rafts during liver regeneration. Nat Commun 2022; 13:6219. [PMID: 36266314 PMCID: PMC9585078 DOI: 10.1038/s41467-022-33969-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 10/07/2022] [Indexed: 12/24/2022] Open
Abstract
Prominin-1, a lipid raft protein, is required for maintaining cancer stem cell properties in hepatocarcinoma cell lines, but its physiological roles in the liver have not been well studied. Here, we investigate the role of Prominin-1 in lipid rafts during liver regeneration and show that expression of Prominin-1 increases after 2/3 partial hepatectomy or CCl4 injection. Hepatocyte proliferation and liver regeneration are attenuated in liver-specific Prominin-1 knockout mice compared to wild-type mice. Detailed mechanistic studies reveal that Prominin-1 interacts with the interleukin-6 signal transducer glycoprotein 130, confining it to lipid rafts so that STAT3 signaling by IL-6 is effectively activated. The overexpression of the glycosylphosphatidylinsositol-anchored first extracellular domain of Prominin-1, which is the domain that binds to GP130, rescued the proliferation of hepatocytes and liver regeneration in liver-specific Prominin-1 knockout mice. In summary, Prominin-1 is upregulated in hepatocytes during liver regeneration where it recruits GP130 into lipid rafts and activates the IL6-GP130-STAT3 axis, suggesting that Prominin-1 might be a promising target for therapeutic applications in liver transplantation.
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13
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Pandrangi SL, Chittineedi P, Chalumuri SS, Meena AS, Neira Mosquera JA, Sánchez Llaguno SN, Pamuru RR, Mohiddin GJ, Mohammad A. Role of Intracellular Iron in Switching Apoptosis to Ferroptosis to Target Therapy-Resistant Cancer Stem Cells. Molecules 2022; 27:3011. [PMID: 35566360 PMCID: PMC9100132 DOI: 10.3390/molecules27093011] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 04/30/2022] [Accepted: 05/02/2022] [Indexed: 02/07/2023] Open
Abstract
Iron is a crucial element required for the proper functioning of the body. For instance, hemoglobin is the vital component in the blood that delivers oxygen to various parts of the body. The heme protein present in hemoglobin comprises iron in the form of a ferrous state which regulates oxygen delivery. Excess iron in the body is stored as ferritin and would be utilized under iron-deficient conditions. Surprisingly, cancer cells as well as cancer stem cells have elevated ferritin levels suggesting that iron plays a vital role in protecting these cells. However, apart from the cytoprotective role iron also has the potential to induce cell death via ferroptosis which is a non-apoptotic cell death dependent on iron reserves. Apoptosis a caspase-dependent cell death mechanism is effective on cancer cells however little is known about its impact on cancer stem cell death. This paper focuses on the molecular characteristics of apoptosis and ferroptosis and the importance of switching to ferroptosis to target cancer stem cells death thereby preventing cancer relapse. To the best of our knowledge, this is the first review to demonstrate the importance of intracellular iron in regulating the switching of tumor cells and therapy resistant CSCs from apoptosis to ferroptosis.
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Affiliation(s)
- Santhi Latha Pandrangi
- Onco-Stem Cell Research Laboratory, Department of Biochemistry and Bioinformatics, Institute of Science, GITAM Deemed to be University, Visakhapatnam 530045, India; (P.C.); (S.S.C.)
| | - Prasanthi Chittineedi
- Onco-Stem Cell Research Laboratory, Department of Biochemistry and Bioinformatics, Institute of Science, GITAM Deemed to be University, Visakhapatnam 530045, India; (P.C.); (S.S.C.)
| | - Sphoorthi Shree Chalumuri
- Onco-Stem Cell Research Laboratory, Department of Biochemistry and Bioinformatics, Institute of Science, GITAM Deemed to be University, Visakhapatnam 530045, India; (P.C.); (S.S.C.)
| | - Avtar Singh Meena
- CSIR-Centre for Cellular and Molecular Biology (CCMB), Hyderabad 500007, India;
| | - Juan Alejandro Neira Mosquera
- Department of Life Sciences and Agriculture, Armed Forces University-ESPE, Santo Domingo 230101, Ecuador; (J.A.N.M.); (S.N.S.L.)
- Faculty of Industry and Production Sciences, Quevedo State Technical University, km 11/2 via Santo Domingo, Quevedo 120301, Ecuador
| | - Sungey Naynee Sánchez Llaguno
- Department of Life Sciences and Agriculture, Armed Forces University-ESPE, Santo Domingo 230101, Ecuador; (J.A.N.M.); (S.N.S.L.)
| | | | - Gooty Jaffer Mohiddin
- Department of Life Sciences and Agriculture, Armed Forces University-ESPE, Santo Domingo 230101, Ecuador; (J.A.N.M.); (S.N.S.L.)
| | - Arifullah Mohammad
- Department of Agriculture Science, Faculty of Agro-Based Industry, Universiti Malaysia Kelantan, Jeli 17600, Malaysia
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14
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Transcriptomic Crosstalk between Gliomas and Telencephalic Neural Stem and Progenitor Cells for Defining Heterogeneity and Targeted Signaling Pathways. Int J Mol Sci 2021; 22:ijms222413211. [PMID: 34948008 PMCID: PMC8703403 DOI: 10.3390/ijms222413211] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 11/29/2021] [Accepted: 11/30/2021] [Indexed: 12/15/2022] Open
Abstract
Recent studies have begun to reveal surprising levels of cell diversity in the human brain, both in adults and during development. Distinctive cellular phenotypes point to complex molecular profiles, cellular hierarchies and signaling pathways in neural stem cells, progenitor cells, neuronal and glial cells. Several recent reports have suggested that neural stem and progenitor cell types found in the developing and adult brain share several properties and phenotypes with cells from brain primary tumors, such as gliomas. This transcriptomic crosstalk may help us to better understand the cell hierarchies and signaling pathways in both gliomas and the normal brain, and, by clarifying the phenotypes of cells at the origin of the tumor, to therapeutically address their most relevant signaling pathways.
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15
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Sung K, Hosoya K, Murase Y, Deguchi T, Kim S, Sunaga T, Okumura M. Visualizing the cancer stem-like properties of canine tumour cells with low proteasome activity. Vet Comp Oncol 2021; 20:324-335. [PMID: 34719098 DOI: 10.1111/vco.12779] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 10/15/2021] [Indexed: 11/26/2022]
Abstract
Cancer stem-like cells (CSCs) cause treatment failure in various tumours; however, establishing CSC-targeted therapies has been hampered by difficulties in the identification and isolation of this small sub-population of cells. Recent studies have revealed that tumour cells with low proteasome activity display a CSC phenotype that can be utilized to image CSCs in canines. This study visualizes and reveals the CSC-like properties of tumour cells with low proteasome activity in HMPOS (osteosarcoma) and MegTCC (transitional cell carcinoma), which are canine cell lines. The parent cells were genetically engineered to express ZsGreen1, a fluorescent protein connected to the carboxyl-terminal degron of canine ornithine decarboxylase that accumulates with low proteasome activity (ZsG+ cells). ZsG+ cells were imaged and the mode of action of this system was confirmed using a proteasome inhibitor (MG-132), which increased the ZsGreen1 fluorescence intensity. The CSC-like properties of ZsG+ cells were evaluated on the basis of cell divisions, cell cycle, the expression of CSC markers and tumourigenicity. ZsG+ cells underwent asymmetric divisions and had a low percentage of G0/G1 phase cells; moreover, ZsG+ cells expressed CSC markers such as CD133 and showed a large tumourigenic capability. In histopathological analysis, ZsG+ cells were widely distributed in the tumour samples derived from ZsG+ cells and in the proliferative regions of the tumours. The results of this study indicate that visualized canine tumour cells with low proteasome activity have a CSC-like phenotype and that this visualization system can be utilized to identify and isolate canine CSCs.
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Affiliation(s)
- Koangyong Sung
- Laboratory of Veterinary Surgery, Department of Veterinary Clinical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan
| | - Kenji Hosoya
- Veterinary Teaching Hospital, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan
| | - Yusuke Murase
- Laboratory of Veterinary Surgery, Department of Veterinary Clinical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan
| | - Tatsuya Deguchi
- Veterinary Teaching Hospital, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan
| | - Sangho Kim
- Laboratory of Veterinary Surgery, Department of Veterinary Clinical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan
| | - Takafumi Sunaga
- Laboratory of Veterinary Surgery, Department of Veterinary Clinical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan
| | - Masahiro Okumura
- Laboratory of Veterinary Surgery, Department of Veterinary Clinical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan
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16
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Bittenglova K, Habart D, Saudek F, Koblas T. The Potential of Pancreatic Organoids for Diabetes Research and Therapy. Islets 2021; 13:85-105. [PMID: 34523383 PMCID: PMC8528407 DOI: 10.1080/19382014.2021.1941555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 06/04/2021] [Indexed: 10/20/2022] Open
Abstract
The success of clinical transplantation of pancreas or isolated pancreatic islets supports the concept of cell-based cure for diabetes. One limitation is the shortage of cadaver human pancreata. The demand-supply gap could potentially be bridged by harnessing the self-renewal capacity of stem cells. Pluripotent stem cells and adult pancreatic stem cells have been explored as possible cell sources. Recently, a system for long-term culture of proposed adult pancreatic stem cells in a form of organoids was developed. Generated organoids partially mimic the architecture and cell-type composition of pancreatic tissue. Here, we review the attempts over the past decade, to utilize the organoid cell culture principles in order to identify, expand, and differentiate the adult pancreatic stem cells from different compartments of mouse and human pancreata. The development of the culture conditions, effects of specific growth factors and small molecules is discussed. The potential utility of the adult pancreatic stem cells is considered in the context of other cell sources.
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Affiliation(s)
- Katerina Bittenglova
- Department of Diabetes, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
- First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - David Habart
- Department of Diabetes, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Frantisek Saudek
- Department of Diabetes, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Tomas Koblas
- Department of Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
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Kordes C, Bock HH, Reichert D, May P, Häussinger D. Hepatic stellate cells: current state and open questions. Biol Chem 2021; 402:1021-1032. [PMID: 34008380 DOI: 10.1515/hsz-2021-0180] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 05/03/2021] [Indexed: 01/14/2023]
Abstract
This review article summarizes 20 years of our research on hepatic stellate cells within the framework of two collaborative research centers CRC575 and CRC974 at the Heinrich Heine University. Over this period, stellate cells were identified for the first time as mesenchymal stem cells of the liver, and important functions of these cells in the context of liver regeneration were discovered. Furthermore, it was determined that the space of Disse - bounded by the sinusoidal endothelium and hepatocytes - functions as a stem cell niche for stellate cells. Essential elements of this niche that control the maintenance of hepatic stellate cells have been identified alongside their impairment with age. This article aims to highlight previous studies on stellate cells and critically examine and identify open questions and future research directions.
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Affiliation(s)
- Claus Kordes
- Clinic of Gastroenterology, Hepatology, and Infectious Diseases, Heinrich Heine University, Moorenstraße 5, D-40225 Düsseldorf, Germany
| | - Hans H Bock
- Clinic of Gastroenterology, Hepatology, and Infectious Diseases, Heinrich Heine University, Moorenstraße 5, D-40225 Düsseldorf, Germany
| | - Doreen Reichert
- Clinic of Gastroenterology, Hepatology, and Infectious Diseases, Heinrich Heine University, Moorenstraße 5, D-40225 Düsseldorf, Germany
| | - Petra May
- Clinic of Gastroenterology, Hepatology, and Infectious Diseases, Heinrich Heine University, Moorenstraße 5, D-40225 Düsseldorf, Germany
| | - Dieter Häussinger
- Clinic of Gastroenterology, Hepatology, and Infectious Diseases, Heinrich Heine University, Moorenstraße 5, D-40225 Düsseldorf, Germany
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18
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Javed S, Sood S, Rai B, Bhattacharyya S, Bagga R, Srinivasan R. ALDH1 & CD133 in invasive cervical carcinoma & their association with the outcome of chemoradiation therapy. Indian J Med Res 2021; 154:367-374. [PMID: 35229742 PMCID: PMC9131751 DOI: 10.4103/ijmr.ijmr_709_20] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Background & objectives: Chemoradiation is the standard therapy for locally advanced invasive cervical cancer and response to treatment determines the outcome. Cancer stem cells (CSCs) and epithelial–mesenchymal transition (EMT) play a role in response to treatment and hence the aim of this study was to evaluate if their levels in pre-treatment biopsies by immunohistochemistry (IHC) could predict response to treatment and outcome. Methods: The study comprised 60 patients with FIGO Stage IIB/III invasive cervical carcinoma treated by chemoradiation. They were divided into two groups based on their clinical outcome: group 1, 30 patients who had no evidence of disease at 48 month follow up and group 2, 30 patients who had disease relapse within 6-12 months of treatment completion. IHC was performed for CSC markers (ALDH1, CD133, Nanog and Oct-4), EMT markers (E-cadherin and vimentin) and squamocolumnar junction (KRT7) markers and H-scores determined. Intergroup comparison was performed. The expression of these markers was also evaluated in histological sections of cervical pre-cancer (CIN1 and CIN3) in comparison to normal cervix. Results: Cervical Intraepithelial Neoplasia grade 3 (CIN3) showed high expression of ALDH1 and KRT7 as compared to normal cervical epithelium. Aldehyde dehydrogenase 1 (ALDH1) and CD133 were overexpressed in 70 and 24 per cent cervical carcinoma cases whereas E-cadherin showed reduced expression in invasive carcinoma as compared to normal controls. ALDH1 overexpression was significantly associated with disease relapse in invasive cervical carcinoma treated by chemoradiation (P<0.01). Interpretation & conclusions: Determination of ALDH1 levels in pre-treatment cervical biopsies of invasive cervical carcinoma may be useful for prediction of response to chemoradiation, with high levels predicting for a poor response.
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Affiliation(s)
- Shifa Javed
- Department of Cytology & Gynecological Pathology, Postgraduate Institute of Medical Education & Research, Chandigarh, India
| | - Swati Sood
- Department of Cytology & Gynecological Pathology, Postgraduate Institute of Medical Education & Research, Chandigarh, India
| | - Bhavana Rai
- Department of Radiation Therapy & Oncology, Postgraduate Institute of Medical Education & Research, Chandigarh, India
| | - Shalmoli Bhattacharyya
- Department of Biophysics, Postgraduate Institute of Medical Education & Research, Chandigarh, India
| | - Rashmi Bagga
- Department of Obstetrics & Gynecology, Postgraduate Institute of Medical Education & Research, Chandigarh, India
| | - Radhika Srinivasan
- Department of Cytology & Gynecological Pathology, Postgraduate Institute of Medical Education & Research, Chandigarh, India
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Bobinger T, Roeder SS, Spruegel MI, Froehlich K, Beuscher VD, Hoelter P, Lücking H, Corbeil D, Huttner HB. Variation of membrane particle-bound CD133 in cerebrospinal fluid of patients with subarachnoid and intracerebral hemorrhage. J Neurosurg 2021; 134:600-607. [PMID: 31978876 DOI: 10.3171/2019.11.jns191861] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Accepted: 11/25/2019] [Indexed: 11/06/2022]
Abstract
OBJECTIVE Previous studies have demonstrated that human CSF contains membrane particles carrying the stem cell antigenic marker CD133 (prominin-1). Here, the authors analyzed the variation of the amount of these CD133-positive particles in the CSF of patients with subarachnoid hemorrhage (SAH) and intracerebral hemorrhage (ICH). METHODS Consecutive CSF samples from 47 patients with SAH or ICH were compared to 14 healthy control patients. After differential ultracentrifugation of CSF, the membrane particle fraction was separated on gel electrophoresis and its CD133 content was probed by immunoblotting using the mouse monoclonal antibody 80B258 directed against human CD133. The antigen-antibody complexes were detected by chemiluminescence reagents and quantified using human Caco-2 cell extract as positive control with a standardized curve. RESULTS As compared to healthy controls (6.3 ± 0.5 ng of bound CD133 antibody; n = 14), the amount of membrane particle-associated CD133 immunoreactivities was significantly elevated in patients with SAH and ICH (38.2 ± 6.6 ng and 61.3 ± 11.0 ng [p < 0.001] for SAH [n = 18] and ICH [n = 29], respectively). In both groups the CD133 level dropped during the first 7 days (i.e., day 5-7: SAH group, 24.6 ± 10.1 ng [p = 0.06]; ICH group, 25.0 ± 4.8 ng [p = 0.002]). Whereas changes in the amount of CD133-positive membrane particles between admission and day 5-7 were not associated with clinical outcomes in patients with ICH (modified Rankin Scale [mRS] scores 0-3, -30.9 ± 12.8 ng vs mRS scores 4-6, -21.8 ± 10.7 ng; p = 0.239), persistent elevation of CD133 in patients with SAH was related to impaired functional outcome 3 months after ictus (mRS scores 0-2, -29.9 ± 8.1 ng vs mRS scores 3-6, 7.6 ± 20.3 ng; p = 0.027). These data are expressed as the mean ± standard error of the mean (SEM). CONCLUSIONS Levels of membrane particle-associated CD133 in the CSF of patients with SAH and ICH are significantly increased in comparison to healthy patients, and they decline during the hospital stay. Specifically, the persistent elevation of CD133-positive membrane particles within the first week may represent a possible surrogate measure for impaired functional outcome in patients with SAH.
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Affiliation(s)
| | | | | | | | | | - Philip Hoelter
- 2Neuroradiology, Friedrich-Alexander University Erlangen (FAU); and
| | - Hannes Lücking
- 2Neuroradiology, Friedrich-Alexander University Erlangen (FAU); and
| | - Denis Corbeil
- 3Biotechnology Center (BIOTEC), Technische Universität Dresden, Germany
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20
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Lee H, Yu D, Park JS, Lee H, Kim J, Kim HL, Koo S, Lee J, Lee S, Ko Y. Prominin-1-Radixin axis controls hepatic gluconeogenesis by regulating PKA activity. EMBO Rep 2020; 21:e49416. [PMID: 33030802 PMCID: PMC7645247 DOI: 10.15252/embr.201949416] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Revised: 08/31/2020] [Accepted: 09/10/2020] [Indexed: 12/18/2022] Open
Abstract
Prominin-1 (Prom1) is a major cell surface marker of cancer stem cells, but its physiological functions in the liver have not been elucidated. We analyzed the levels of mRNA transcripts in serum-starved primary WT (Prom1+/+ ) and KO (Prom1-/- ) mouse hepatocytes using RNA sequencing (RNA-seq) data, and found that CREB target genes were downregulated. This initial observation led us to determine that Prom1 deficiency inhibited cAMP response element-binding protein (CREB) activation and gluconeogenesis, but not cyclic AMP (cAMP) accumulation, in glucagon-, epinephrine-, or forskolin-treated liver tissues and primary hepatocytes, and mitigated glucagon-induced hyperglycemia. Because Prom1 interacted with radixin, Prom1 deficiency prevented radixin from localizing to the plasma membrane. Moreover, systemic adenoviral knockdown of radixin inhibited CREB activation and gluconeogenesis in glucagon-treated liver tissues and primary hepatocytes, and mitigated glucagon-elicited hyperglycemia. Based on these results, we conclude that Prom1 regulates hepatic PKA signaling via radixin functioning as an A kinase-anchored protein (AKAP).
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Affiliation(s)
- Hyun Lee
- Tunneling Nanotube Research CenterKorea UniversitySeoulKorea
- Division of Life SciencesKorea UniversitySeoulKorea
| | - Dong‐Min Yu
- Tunneling Nanotube Research CenterKorea UniversitySeoulKorea
- Division of Life SciencesKorea UniversitySeoulKorea
| | - Jun Sub Park
- Tunneling Nanotube Research CenterKorea UniversitySeoulKorea
- Division of Life SciencesKorea UniversitySeoulKorea
| | - Hwayeon Lee
- Tunneling Nanotube Research CenterKorea UniversitySeoulKorea
- Division of Life SciencesKorea UniversitySeoulKorea
| | - Jun‐Seok Kim
- Tunneling Nanotube Research CenterKorea UniversitySeoulKorea
- Division of Life SciencesKorea UniversitySeoulKorea
| | - Hong Lim Kim
- Laboratory of Electron MicroscopeIntegrative Research Support CenterCollege of MedicineThe Catholic University of KoreaSeoulKorea
| | - Seung‐Hoi Koo
- Tunneling Nanotube Research CenterKorea UniversitySeoulKorea
- Division of Life SciencesKorea UniversitySeoulKorea
| | - Jae‐Seon Lee
- Department of Molecular MedicineInha University College of MedicineIncheonKorea
- Hypoxia‐related Disease Research CenterInha University College of MedicineIncheonKorea
| | - Sungsoo Lee
- Tunneling Nanotube Research CenterKorea UniversitySeoulKorea
- Division of Life SciencesKorea UniversitySeoulKorea
| | - Young‐Gyu Ko
- Tunneling Nanotube Research CenterKorea UniversitySeoulKorea
- Division of Life SciencesKorea UniversitySeoulKorea
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21
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Vora P, Venugopal C, Salim SK, Tatari N, Bakhshinyan D, Singh M, Seyfrid M, Upreti D, Rentas S, Wong N, Williams R, Qazi MA, Chokshi C, Ding A, Subapanditha M, Savage N, Mahendram S, Ford E, Adile AA, McKenna D, McFarlane N, Huynh V, Wylie RG, Pan J, Bramson J, Hope K, Moffat J, Singh S. The Rational Development of CD133-Targeting Immunotherapies for Glioblastoma. Cell Stem Cell 2020; 26:832-844.e6. [PMID: 32464096 DOI: 10.1016/j.stem.2020.04.008] [Citation(s) in RCA: 129] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Revised: 12/16/2019] [Accepted: 04/14/2020] [Indexed: 01/01/2023]
Abstract
CD133 marks self-renewing cancer stem cells (CSCs) in a variety of solid tumors, and CD133+ tumor-initiating cells are known markers of chemo- and radio-resistance in multiple aggressive cancers, including glioblastoma (GBM), that may drive intra-tumoral heterogeneity. Here, we report three immunotherapeutic modalities based on a human anti-CD133 antibody fragment that targets a unique epitope present in glycosylated and non-glycosylated CD133 and studied their effects on targeting CD133+ cells in patient-derived models of GBM. We generated an immunoglobulin G (IgG) (RW03-IgG), a dual-antigen T cell engager (DATE), and a CD133-specific chimeric antigen receptor T cell (CAR-T): CART133. All three showed activity against patient-derived CD133+ GBM cells, and CART133 cells demonstrated superior efficacy in patient-derived GBM xenograft models without causing adverse effects on normal CD133+ hematopoietic stem cells in humanized CD34+ mice. Thus, CART133 cells may be a therapeutically tractable strategy to target CD133+ CSCs in human GBM or other treatment-resistant primary cancers.
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Affiliation(s)
- Parvez Vora
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada; Surgery, Faculty of Health Sciences, McMaster University, 1200 Main Street West, Hamilton, ON L8N 3Z5, Canada
| | - Chitra Venugopal
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada; Surgery, Faculty of Health Sciences, McMaster University, 1200 Main Street West, Hamilton, ON L8N 3Z5, Canada
| | - Sabra Khalid Salim
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada; Departments of Biochemistry and Biomedical Sciences, McMaster University, 1200 Main Street West, Hamilton, ON L8N 3Z5, Canada
| | - Nazanin Tatari
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada; Departments of Biochemistry and Biomedical Sciences, McMaster University, 1200 Main Street West, Hamilton, ON L8N 3Z5, Canada
| | - David Bakhshinyan
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada; Departments of Biochemistry and Biomedical Sciences, McMaster University, 1200 Main Street West, Hamilton, ON L8N 3Z5, Canada
| | - Mohini Singh
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada; Departments of Biochemistry and Biomedical Sciences, McMaster University, 1200 Main Street West, Hamilton, ON L8N 3Z5, Canada
| | - Mathieu Seyfrid
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada; Surgery, Faculty of Health Sciences, McMaster University, 1200 Main Street West, Hamilton, ON L8N 3Z5, Canada
| | - Deepak Upreti
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada; Surgery, Faculty of Health Sciences, McMaster University, 1200 Main Street West, Hamilton, ON L8N 3Z5, Canada
| | - Stefan Rentas
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada; Departments of Biochemistry and Biomedical Sciences, McMaster University, 1200 Main Street West, Hamilton, ON L8N 3Z5, Canada
| | - Nicholas Wong
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada
| | - Rashida Williams
- Donnelly Centre, Department of Molecular Genetics, Institute of Biomolecular Engineering, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada
| | - Maleeha Ahmad Qazi
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada; Departments of Biochemistry and Biomedical Sciences, McMaster University, 1200 Main Street West, Hamilton, ON L8N 3Z5, Canada
| | - Chirayu Chokshi
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada; Departments of Biochemistry and Biomedical Sciences, McMaster University, 1200 Main Street West, Hamilton, ON L8N 3Z5, Canada
| | - Avrilynn Ding
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada
| | - Minomi Subapanditha
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada
| | - Neil Savage
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada; Departments of Biochemistry and Biomedical Sciences, McMaster University, 1200 Main Street West, Hamilton, ON L8N 3Z5, Canada
| | - Sujeivan Mahendram
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada; Surgery, Faculty of Health Sciences, McMaster University, 1200 Main Street West, Hamilton, ON L8N 3Z5, Canada
| | - Emily Ford
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada
| | - Ashley Ann Adile
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada; Departments of Biochemistry and Biomedical Sciences, McMaster University, 1200 Main Street West, Hamilton, ON L8N 3Z5, Canada
| | - Dillon McKenna
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada; Surgery, Faculty of Health Sciences, McMaster University, 1200 Main Street West, Hamilton, ON L8N 3Z5, Canada
| | - Nicole McFarlane
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada
| | - Vince Huynh
- Department of Chemistry and Chemical Biology, McMaster University, Hamilton ON L8S 4M1, Canada
| | - Ryan Gavin Wylie
- Department of Chemistry and Chemical Biology, McMaster University, Hamilton ON L8S 4M1, Canada
| | - James Pan
- Donnelly Centre, Department of Molecular Genetics, Institute of Biomolecular Engineering, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada
| | - Jonathan Bramson
- Department of Pathology and Molecular Medicine, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada
| | - Kristin Hope
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada
| | - Jason Moffat
- Donnelly Centre, Department of Molecular Genetics, Institute of Biomolecular Engineering, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada.
| | - Sheila Singh
- McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada; Departments of Biochemistry and Biomedical Sciences, McMaster University, 1200 Main Street West, Hamilton, ON L8N 3Z5, Canada; Surgery, Faculty of Health Sciences, McMaster University, 1200 Main Street West, Hamilton, ON L8N 3Z5, Canada.
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22
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Jászai J, Thamm K, Karbanová J, Janich P, Fargeas CA, Huttner WB, Corbeil D. Prominins control ciliary length throughout the animal kingdom: New lessons from human prominin-1 and zebrafish prominin-3. J Biol Chem 2020; 295:6007-6022. [PMID: 32201384 DOI: 10.1074/jbc.ra119.011253] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 03/18/2020] [Indexed: 01/18/2023] Open
Abstract
Prominins (proms) are transmembrane glycoproteins conserved throughout the animal kingdom. They are associated with plasma membrane protrusions, such as primary cilia, as well as extracellular vesicles derived thereof. Primary cilia host numerous signaling pathways affected in diseases known as ciliopathies. Human PROM1 (CD133) is detected in both somatic and cancer stem cells and is also expressed in terminally differentiated epithelial and photoreceptor cells. Genetic mutations in the PROM1 gene result in retinal degeneration by impairing the proper formation of the outer segment of photoreceptors, a modified cilium. Here, we investigated the impact of proms on two distinct examples of ciliogenesis. First, we demonstrate that the overexpression of a dominant-negative mutant variant of human PROM1 (i.e. mutation Y819F/Y828F) significantly decreases ciliary length in Madin-Darby canine kidney cells. These results contrast strongly to the previously observed enhancing effect of WT PROM1 on ciliary length. Mechanistically, the mutation impeded the interaction of PROM1 with ADP-ribosylation factor-like protein 13B, a key regulator of ciliary length. Second, we observed that in vivo knockdown of prom3 in zebrafish alters the number and length of monocilia in the Kupffer's vesicle, resulting in molecular and anatomical defects in the left-right asymmetry. These distinct loss-of-function approaches in two biological systems reveal that prom proteins are critical for the integrity and function of cilia. Our data provide new insights into ciliogenesis and might be of particular interest for investigations of the etiologies of ciliopathies.
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Affiliation(s)
- József Jászai
- Tissue Engineering Laboratories, Biotechnology Center (BIOTEC) and Center for Molecular and Cellular Bioengineering, Technische Universität Dresden, Tatzberg 47-49, 01307 Dresden, Germany; Institute of Anatomy, Medizinische Fakultät der Technischen Universität Dresden, Fiedlerstrasse 42, 01307 Dresden, Germany.
| | - Kristina Thamm
- Tissue Engineering Laboratories, Biotechnology Center (BIOTEC) and Center for Molecular and Cellular Bioengineering, Technische Universität Dresden, Tatzberg 47-49, 01307 Dresden, Germany
| | - Jana Karbanová
- Tissue Engineering Laboratories, Biotechnology Center (BIOTEC) and Center for Molecular and Cellular Bioengineering, Technische Universität Dresden, Tatzberg 47-49, 01307 Dresden, Germany
| | - Peggy Janich
- Tissue Engineering Laboratories, Biotechnology Center (BIOTEC) and Center for Molecular and Cellular Bioengineering, Technische Universität Dresden, Tatzberg 47-49, 01307 Dresden, Germany
| | - Christine A Fargeas
- Tissue Engineering Laboratories, Biotechnology Center (BIOTEC) and Center for Molecular and Cellular Bioengineering, Technische Universität Dresden, Tatzberg 47-49, 01307 Dresden, Germany
| | - Wieland B Huttner
- Max-Planck-Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany
| | - Denis Corbeil
- Tissue Engineering Laboratories, Biotechnology Center (BIOTEC) and Center for Molecular and Cellular Bioengineering, Technische Universität Dresden, Tatzberg 47-49, 01307 Dresden, Germany.
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23
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Akbari M, Shomali N, Faraji A, Shanehbandi D, Asadi M, Mokhtarzadeh A, Shabani A, Baradaran B. CD133: An emerging prognostic factor and therapeutic target in colorectal cancer. Cell Biol Int 2019; 44:368-380. [PMID: 31579983 DOI: 10.1002/cbin.11243] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Accepted: 09/29/2019] [Indexed: 12/12/2022]
Abstract
Colorectal cancer (CRC) is one of the leading causes of death worldwide. Recently, the role of cancer stem cells (CSCs) has been highlighted as a crucial emerging factor in chemoresistance, cancer relapse, and metastasis. CD133 is a surface marker of CSCs and has been argued to have prognostic and therapeutic values in CRC along with its related pathways such as Wnt, Notch, and hedgehog. Several studies have successfully applied targeted therapies against CD133 in CRC models namely bispecific antibodies (BiAbs) and anti-Wnt and notch pathways agents. These studies have yielded initial promising results in this regard. However, none of the therapeutics have been used in the clinical setting and their efficacy and adverse effects profile are yet to be elucidated. This review aims to gather the old and most recent data on the prognostic and therapeutic values of CD133 and CD133-targeted therapies in CRC.
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Affiliation(s)
- Morteza Akbari
- Department of Biotechnology, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, 3514799422, Iran.,Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, 5166614766, Iran.,Semnan Biotechnology Research Center, Semnan University of Medical sciences, Semnan, 3514799422, Iran
| | - Navid Shomali
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, 5166614766, Iran.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, 5166614766, Iran.,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, 5166614766, Iran
| | - Afsaneh Faraji
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, 5166614766, Iran
| | - Dariush Shanehbandi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, 5166614766, Iran
| | - Milad Asadi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, 5166614766, Iran
| | - Ahad Mokhtarzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, 5166614766, Iran
| | - Aliakbar Shabani
- Semnan Biotechnology Research Center, Semnan University of Medical sciences, Semnan, 3514799422, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, 5166614766, Iran
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24
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Tanaka J, Mishima K. Reply to Karbanová et al.: Prominin-1/CD133, saliva and salivary glands - Integrating existing data to new clinical approaches. Exp Cell Res 2019; 383:111567. [PMID: 31446163 DOI: 10.1016/j.yexcr.2019.111567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Accepted: 08/19/2019] [Indexed: 10/26/2022]
Affiliation(s)
- Junichi Tanaka
- Division of Pathology, Department of Oral Diagnostic Sciences, School of Dentistry, Showa University, Tokyo, 142-8555, Japan
| | - Kenji Mishima
- Division of Pathology, Department of Oral Diagnostic Sciences, School of Dentistry, Showa University, Tokyo, 142-8555, Japan.
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25
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Karbanová J, Corbeil D, Fargeas CA. Prominin-1/CD133, saliva and salivary glands - Integrating existing data to new clinical approaches. Exp Cell Res 2019; 383:111566. [PMID: 31470017 DOI: 10.1016/j.yexcr.2019.111566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Accepted: 08/19/2019] [Indexed: 11/30/2022]
Affiliation(s)
- Jana Karbanová
- Tissue Engineering Laboratories, Biotechnology Center (BIOTEC), Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden, Tatzberg 47-49, 01307, Dresden, Germany
| | - Denis Corbeil
- Tissue Engineering Laboratories, Biotechnology Center (BIOTEC), Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden, Tatzberg 47-49, 01307, Dresden, Germany.
| | - Christine A Fargeas
- Tissue Engineering Laboratories, Biotechnology Center (BIOTEC), Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden, Tatzberg 47-49, 01307, Dresden, Germany
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26
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Dietrich J, Schrader S. Towards Lacrimal Gland Regeneration: Current Concepts and Experimental Approaches. Curr Eye Res 2019; 45:230-240. [PMID: 31246108 DOI: 10.1080/02713683.2019.1637438] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Dry eye disease (DED) is a complex and multifactorial disease resulting in a continual cycle of tear hyperosmolarity and inflammation. Patients suffering from DED experience severe pain and visual impairments leading to a reduced quality of life. Aqueous-deficient dry eye (ADDE), mainly caused through a loss of functional lacrimal gland tissue, results in the most severe forms of DED. Despite a high prevalence, the current treatments remain palliative and may be insufficient to alleviate the symptoms. Consequently, investigations on experimental approaches for in situ lacrimal gland regeneration are of great clinical interest. This article reviews the current knowledge about processes involved in lacrimal gland regeneration, about lacrimal gland resident stem cells, and offers deductions about possible concepts for in situ lacrimal gland regeneration. Promising starting points might be the utilization of therapeutic proteins, such as bone morphogenetic protein 7, mesenchymal stem cells (MSC) or MSC-based treatments such as conditioned medium, lyophilized cell extracts or adult acinar cells. This review further summarizes current experimental approaches for the treatment of ADDE in animal models and patients. Approaches investigating side population stem cells, epithelial progenitor cells and MSC showed that the transplantation of these cells had therapeutic effects on ADDE. However, the most promising and best-studied experimental approach is the use of MSC for induction/enhancement of in situ lacrimal gland regeneration. Their immunomodulatory effects, low immunogenicity, promotion of tissue regeneration and involvement during spontaneous lacrimal regeneration are favorable traits for clinical applications. In addition, the efficacy and safety of allogeneic MSC transplantation have already been demonstrated in a small patient cohort.
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Affiliation(s)
- Jana Dietrich
- Department of Ophthalmology, Laboratory of Experimental Ophthalmology, PIUS-HOSPITAL, Carl-von-Ossietzky University, Oldenburg, Germany
| | - Stefan Schrader
- Department of Ophthalmology, Laboratory of Experimental Ophthalmology, PIUS-HOSPITAL, Carl-von-Ossietzky University, Oldenburg, Germany
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27
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Yukselten Y, Aydos OSE, Sunguroglu A, Aydos K. Investigation of CD133 and CD24 as candidate azoospermia markers and their relationship with spermatogenesis defects. Gene 2019; 706:211-221. [PMID: 31054360 DOI: 10.1016/j.gene.2019.04.028] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Revised: 03/07/2019] [Accepted: 04/09/2019] [Indexed: 12/21/2022]
Affiliation(s)
- Yunus Yukselten
- Department of Medical Biology, School of Medicine, Ankara University, 06100 Ankara, Turkey; Research Laboratories for Health Science, Y Gen Biotechnology Company Ltd., 06110 Ankara, Turkey
| | - O Sena E Aydos
- Department of Medical Biology, School of Medicine, Ankara University, 06100 Ankara, Turkey.
| | - Asuman Sunguroglu
- Department of Medical Biology, School of Medicine, Ankara University, 06100 Ankara, Turkey
| | - Kaan Aydos
- Department of Urology, School of Medicine, Ankara University 06100, Ankara, Turkey
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28
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Assessment of CD133-positive extracellular membrane vesicles in pancreatic cancer ascites and beyond. Med Mol Morphol 2019; 53:60-62. [PMID: 30953194 DOI: 10.1007/s00795-019-00221-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Accepted: 03/26/2019] [Indexed: 10/27/2022]
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29
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Singer D, Thamm K, Zhuang H, Karbanová J, Gao Y, Walker JV, Jin H, Wu X, Coveney CR, Marangoni P, Lu D, Grayson PRC, Gulsen T, Liu KJ, Ardu S, Wann AK, Luo S, Zambon AC, Jetten AM, Tredwin C, Klein OD, Attanasio M, Carmeliet P, Huttner WB, Corbeil D, Hu B. Prominin-1 controls stem cell activation by orchestrating ciliary dynamics. EMBO J 2018; 38:embj.201899845. [PMID: 30523147 PMCID: PMC6331727 DOI: 10.15252/embj.201899845] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Revised: 10/22/2018] [Accepted: 10/23/2018] [Indexed: 01/09/2023] Open
Abstract
Proper temporal and spatial activation of stem cells relies on highly coordinated cell signaling. The primary cilium is the sensory organelle that is responsible for transmitting extracellular signals into a cell. Primary cilium size, architecture, and assembly-disassembly dynamics are under rigid cell cycle-dependent control. Using mouse incisor tooth epithelia as a model, we show that ciliary dynamics in stem cells require the proper functions of a cholesterol-binding membrane glycoprotein, Prominin-1 (Prom1/CD133), which controls sequential recruitment of ciliary membrane components, histone deacetylase, and transcription factors. Nuclear translocation of Prom1 and these molecules is particularly evident in transit amplifying cells, the immediate derivatives of stem cells. The absence of Prom1 impairs ciliary dynamics and abolishes the growth stimulation effects of sonic hedgehog (SHH) treatment, resulting in the disruption of stem cell quiescence maintenance and activation. We propose that Prom1 is a key regulator ensuring appropriate response of stem cells to extracellular signals, with important implications for development, regeneration, and diseases.
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Affiliation(s)
- Donald Singer
- Peninsula Dental School, University of Plymouth, Plymouth, UK
| | - Kristina Thamm
- Tissue Engineering Laboratories, Biotechnology Center and Center for Molecular and Cellular Bioengineering, Technische Universität Dresden, Dresden, Germany
| | - Heng Zhuang
- Peninsula Dental School, University of Plymouth, Plymouth, UK.,Department of Cariology, Endodontology and Operative Dentistry, Peking University School and Hospital of Stomatology, Beijing, China
| | - Jana Karbanová
- Tissue Engineering Laboratories, Biotechnology Center and Center for Molecular and Cellular Bioengineering, Technische Universität Dresden, Dresden, Germany
| | - Yan Gao
- Peninsula Dental School, University of Plymouth, Plymouth, UK.,Department of Orthodontics, School of Stomatology, Capital Medical University, Beijing, China
| | | | - Heng Jin
- Department of Internal Medicine, University of Iowa, Iowa City, IA, USA.,Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin, China
| | - Xiangnan Wu
- Program in Craniofacial Biology and Department of Orofacial Sciences, University of California, San Francisco, CA, USA
| | - Clarissa R Coveney
- Arthritis Research UK Centre for Osteoarthritis Pathogenesis, Kennedy Institute, Nuffield Department for Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford, UK
| | - Pauline Marangoni
- Program in Craniofacial Biology and Department of Orofacial Sciences, University of California, San Francisco, CA, USA
| | - Dongmei Lu
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | | | - Tulay Gulsen
- Peninsula Dental School, University of Plymouth, Plymouth, UK
| | - Karen J Liu
- Centre for Craniofacial and Regenerative Biology, King's College London, London, UK
| | - Stefano Ardu
- Division of Cariology & Endodontology, Dental School, University of Geneva, Geneva, Switzerland
| | - Angus Kt Wann
- Arthritis Research UK Centre for Osteoarthritis Pathogenesis, Kennedy Institute, Nuffield Department for Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford, UK
| | - Shouqing Luo
- Peninsula Medical School, University of Plymouth, Plymouth, UK
| | | | - Anton M Jetten
- Cell Biology Section, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA
| | | | - Ophir D Klein
- Program in Craniofacial Biology and Department of Orofacial Sciences, University of California, San Francisco, CA, USA.,Department of Pediatrics and Institute for Human Genetics, University of California, San Francisco, CA, USA
| | - Massimo Attanasio
- Department of Internal Medicine, University of Iowa, Iowa City, IA, USA
| | - Peter Carmeliet
- Department of Oncology, Laboratory of Angiogenesis and Vascular Metabolism, KU Leuven, Leuven, Belgium.,VIB-KU Leuven Center for Cancer Biology, Leuven, Belgium
| | - Wieland B Huttner
- Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
| | - Denis Corbeil
- Tissue Engineering Laboratories, Biotechnology Center and Center for Molecular and Cellular Bioengineering, Technische Universität Dresden, Dresden, Germany
| | - Bing Hu
- Peninsula Dental School, University of Plymouth, Plymouth, UK
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30
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Thamm K, Šimaitė D, Karbanová J, Bermúdez V, Reichert D, Morgenstern A, Bornhäuser M, Huttner WB, Wilsch‐Bräuninger M, Corbeil D. Prominin‐1 (CD133) modulates the architecture and dynamics of microvilli. Traffic 2018; 20:39-60. [DOI: 10.1111/tra.12618] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Revised: 10/13/2018] [Accepted: 10/14/2018] [Indexed: 12/14/2022]
Affiliation(s)
- Kristina Thamm
- Tissue Engineering LaboratoriesBiotechnology Center and Center for Molecular and Cellular Bioengineering, Technische Universität Dresden Dresden Germany
| | - Deimantė Šimaitė
- Tissue Engineering LaboratoriesBiotechnology Center and Center for Molecular and Cellular Bioengineering, Technische Universität Dresden Dresden Germany
| | - Jana Karbanová
- Tissue Engineering LaboratoriesBiotechnology Center and Center for Molecular and Cellular Bioengineering, Technische Universität Dresden Dresden Germany
| | - Vicente Bermúdez
- Tissue Engineering LaboratoriesBiotechnology Center and Center for Molecular and Cellular Bioengineering, Technische Universität Dresden Dresden Germany
| | - Doreen Reichert
- Tissue Engineering LaboratoriesBiotechnology Center and Center for Molecular and Cellular Bioengineering, Technische Universität Dresden Dresden Germany
| | - Anne Morgenstern
- Tissue Engineering LaboratoriesBiotechnology Center and Center for Molecular and Cellular Bioengineering, Technische Universität Dresden Dresden Germany
| | - Martin Bornhäuser
- Medical Clinic and Polyclinic IUniversity Hospital Carl Gustav Carus Dresden Germany
| | - Wieland B. Huttner
- Max Planck Institute of Molecular Cell Biology and Genetics Dresden Germany
| | | | - Denis Corbeil
- Tissue Engineering LaboratoriesBiotechnology Center and Center for Molecular and Cellular Bioengineering, Technische Universität Dresden Dresden Germany
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31
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Affiliation(s)
- Amir Barzegar Behrooz
- Department of Biochemistry, Faculty of Biotechnology and Biomolecular Science, Universiti Putra Malaysia, Serdang, Malaysia
| | - Amir Syahir
- Department of Biochemistry, Faculty of Biotechnology and Biomolecular Science, Universiti Putra Malaysia, Serdang, Malaysia
| | - Syahida Ahmad
- Department of Biochemistry, Faculty of Biotechnology and Biomolecular Science, Universiti Putra Malaysia, Serdang, Malaysia
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32
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Dowland SN, Madawala RJ, Poon CE, Lindsay LA, Murphy CR. Prominin-1 glycosylation changes throughout early pregnancy in uterine epithelial cells under the influence of maternal ovarian hormones. Reprod Fertil Dev 2018; 29:1194-1208. [PMID: 27166505 DOI: 10.1071/rd15432] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2015] [Accepted: 03/17/2016] [Indexed: 12/29/2022] Open
Abstract
In preparation for uterine receptivity, the uterine epithelial cells (UECs) exhibit a loss of microvilli and glycocalyx and a restructuring of the actin cytoskeleton. The prominin-1 protein contains large, heavily glycosylated extracellular loops and is usually restricted to apical plasma membrane (APM) protrusions. The present study examined rat UECs during early pregnancy using immunofluorescence, western blotting and deglycosylation analyses. Ovariectomised rats were injected with oestrogen and progesterone to examine how these hormones affect prominin-1. At the time of fertilisation, prominin-1 was located diffusely in the apical domain of UECs and 147- and 120-kDa glycoforms of prominin-1 were identified, along with the 97-kDa core protein. At the time of implantation, prominin-1 concentrates towards the APM and densitometry revealed that the 120-kDa glycoform decreased (P<0.05), but there was an increase in the 97-kDa core protein (P<0.05). Progesterone treatment of ovariectomised rats resulted in prominin-1 becoming concentrated towards the APM. The 120-kDa glycoform was increased after oestrogen treatment (P<0.0001), whereas the 97-kDa core protein was increased after progesterone treatment (P<0.05). Endoglycosidase H analysis demonstrated that the 120-kDa glycoform is in the endoplasmic reticulum, undergoing protein synthesis. These results indicate that oestrogen stimulates prominin-1 production, whereas progesterone stimulates the deglycosylation and concentration of prominin-1 to the apical region of the UECs. This likely presents the deglycosylated extracellular loops of prominin-1 to the extracellular space, where they may interact with the implanting blastocyst.
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Affiliation(s)
- Samson N Dowland
- Cell and Reproductive Biology Laboratory, School of Medical Sciences (Discipline of Anatomy and Histology) and The Bosch Institute, Room N364, F13 Anderson Stuart Building, The University of Sydney, NSW 2006, Australia
| | - Romanthi J Madawala
- Cell and Reproductive Biology Laboratory, School of Medical Sciences (Discipline of Anatomy and Histology) and The Bosch Institute, Room N364, F13 Anderson Stuart Building, The University of Sydney, NSW 2006, Australia
| | - Connie E Poon
- Cell and Reproductive Biology Laboratory, School of Medical Sciences (Discipline of Anatomy and Histology) and The Bosch Institute, Room N364, F13 Anderson Stuart Building, The University of Sydney, NSW 2006, Australia
| | - Laura A Lindsay
- Cell and Reproductive Biology Laboratory, School of Medical Sciences (Discipline of Anatomy and Histology) and The Bosch Institute, Room N364, F13 Anderson Stuart Building, The University of Sydney, NSW 2006, Australia
| | - Christopher R Murphy
- Cell and Reproductive Biology Laboratory, School of Medical Sciences (Discipline of Anatomy and Histology) and The Bosch Institute, Room N364, F13 Anderson Stuart Building, The University of Sydney, NSW 2006, Australia
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33
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Glumac PM, LeBeau AM. The role of CD133 in cancer: a concise review. Clin Transl Med 2018; 7:18. [PMID: 29984391 PMCID: PMC6035906 DOI: 10.1186/s40169-018-0198-1] [Citation(s) in RCA: 265] [Impact Index Per Article: 37.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Accepted: 06/16/2018] [Indexed: 12/12/2022] Open
Abstract
Despite the abundant ongoing research efforts, cancer remains one of the most challenging diseases to treat globally. Due to the heterogenous nature of cancer, one of the major clinical challenges in therapeutic development is the cancer’s ability to develop resistance. It has been hypothesized that cancer stem cells are the cause for this resistance, and targeting them will lead to tumor regression. A pentaspan transmembrane glycoprotein, CD133 has been suggested to mark cancer stem cells in various tumor types, however, the accuracy of CD133 as a cancer stem cell biomarker has been highly controversial. There are numerous speculations for this, including differences in cell culture conditions, poor in vivo assays, and the inability of current antibodies to detect CD133 variants and deglycosylated epitopes. This review summarizes the most recent and relevant research regarding the controversies surrounding CD133 as a normal stem cell and cancer stem cell biomarker. Additionally, it aims to establish the overall clinical significance of CD133 in cancer. Recent clinical studies have shown that high expression of CD133 in tumors has been indicated as a prognostic marker of disease progression. As such, a spectrum of immunotherapeutic strategies have been developed to target these CD133pos cells with the goal of translation into the clinic. This review compiles the current therapeutic strategies targeting CD133 and discusses their prognostic potential in various cancer subtypes.
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Affiliation(s)
- Paige M Glumac
- Department of Pharmacology, University of Minnesota Medical School, Nils Hasselmo Hall 3-104, 312 Church St. SE, Minneapolis, MN, 55455, USA
| | - Aaron M LeBeau
- Department of Pharmacology, University of Minnesota Medical School, Nils Hasselmo Hall 3-104, 312 Church St. SE, Minneapolis, MN, 55455, USA.
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34
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Yoshimura H, Matsuda Y, Yamamoto M, Michishita M, Takahashi K, Sasaki N, Ishikawa N, Aida J, Takubo K, Arai T, Ishiwata T. Reduced expression of the H19 long non-coding RNA inhibits pancreatic cancer metastasis. J Transl Med 2018; 98:814-824. [PMID: 29581580 DOI: 10.1038/s41374-018-0048-1] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Revised: 01/23/2018] [Accepted: 01/23/2018] [Indexed: 12/13/2022] Open
Abstract
H19 is an oncofetal RNA expressed in the developing embryo as well as in bladder, breast, gastric, pancreatic, hepatocellular, and prostate cancers. Recent studies have shown that H19 enhances cancer invasion and metastasis; however, its roles in cancer remain controversial. In the current study, H19 exhibited the second largest increase (82.4-fold) and represented the only non-protein coding gene among 11 genes identified that were elevated over 10-fold in lung-metastasis-derived pancreatic cancer cells compared with their parental cells using a mouse metastatic model. Subsequently, we further clarified the roles of H19 in pancreatic cancer growth and metastasis using in vitro and in vivo techniques. In situ hybridization showed that H19 was detected in 23 of 139 invasive ductal carcinomas (17%), and that H19 expression positively correlated with higher histological grades (P < 0.0001). Overexpression of H19 in PANC-1 pancreatic cancer cells induced higher motilities, whereas H19 inhibition using shRNA and siRNA showed opposite results; however, cell growth rates were not impacted. Intravenous injection of H19 shRNA vector-transfected PANC-1 cells yielded marked inhibition of metastasis in the liver and lungs of immunodeficient mice. These findings suggest that H19 has important roles in pancreatic cancer metastasis, and that inhibition of H19 represents a novel candidate for pancreatic cancer therapy.
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Affiliation(s)
- Hisashi Yoshimura
- Division of Physiological Pathology, Department of Applied Science, School of Veterinary Nursing and Technology, Nippon Veterinary and Life Science University, Tokyo, 180-8602, Japan
| | - Yoko Matsuda
- Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Tokyo, 173-0015, Japan
| | - Masami Yamamoto
- Division of Physiological Pathology, Department of Applied Science, School of Veterinary Nursing and Technology, Nippon Veterinary and Life Science University, Tokyo, 180-8602, Japan
| | - Masaki Michishita
- Department of Veterinary Pathology, School of Veterinary Medicine, Nippon Veterinary and Life Science University, Tokyo, 180-8602, Japan
| | - Kimimasa Takahashi
- Department of Veterinary Pathology, School of Veterinary Medicine, Nippon Veterinary and Life Science University, Tokyo, 180-8602, Japan
| | - Norihiko Sasaki
- Research Team for Geriatric Medicine (Vascular Medicine), Tokyo Metropolitan Institute of Gerontology, Tokyo, 173-0015, Japan
| | - Naoshi Ishikawa
- Division of Aging and Carcinogenesis, Research Team for Geriatric Pathology, Tokyo Metropolitan Institute of Gerontology, Tokyo, 173-0015, Japan
| | - Junko Aida
- Division of Aging and Carcinogenesis, Research Team for Geriatric Pathology, Tokyo Metropolitan Institute of Gerontology, Tokyo, 173-0015, Japan
| | - Kaiyo Takubo
- Division of Aging and Carcinogenesis, Research Team for Geriatric Pathology, Tokyo Metropolitan Institute of Gerontology, Tokyo, 173-0015, Japan
| | - Tomio Arai
- Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Tokyo, 173-0015, Japan
| | - Toshiyuki Ishiwata
- Division of Aging and Carcinogenesis, Research Team for Geriatric Pathology, Tokyo Metropolitan Institute of Gerontology, Tokyo, 173-0015, Japan.
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35
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Al-Lamki RS, Wang J, Yang J, Burrows N, Maxwell PH, Eisen T, Warren AY, Vanharanta S, Pacey S, Vandenabeele P, Pober JS, Bradley JR. Tumor necrosis factor receptor 2-signaling in CD133-expressing cells in renal clear cell carcinoma. Oncotarget 2018; 7:24111-24. [PMID: 26992212 PMCID: PMC5029688 DOI: 10.18632/oncotarget.8125] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Accepted: 03/02/2016] [Indexed: 01/29/2023] Open
Abstract
Compared to normal kidney, renal clear cell carcinomas (ccRCC) contain increased numbers of interstitial, non-hematopoietic CD133+cells that express stem cell markers and exhibit low rates of proliferation. These cells fail to form tumors upon transplantation but support tumor formation by differentiated malignant cells. We hypothesized that killing of ccRCC CD133+ (RCCCD133+) cells by cytotoxic agents might be enhanced by inducing them to divide. Since tumor necrosis factor-alpha (TNF), signalling through TNFR2, induces proliferation of malignant renal tubular epithelial cells, we investigated whether TNFR2 might similarly affect RCCCD133+cells. We compared treating organ cultures of ccRCC vs adjacent nontumour kidney (NK) and RCCCD133+vs NK CD133+ (NKCD133+) cell cultures with wild-type TNF (wtTNF) or TNF muteins selective for TNFR1 (R1TNF) or TNFR2 (R2TNF). In organ cultures, R2TNF increased expression of TNFR2 and promoted cell cycle entry of both RCCCD133+ and NKCD133+ but effects were greater in RCCCD133+. In contrast, R1TNF increased TNFR1 expression and promoted cell death. Importantly, cyclophosphamide triggered much more cell death in RCCCD133+ and NKCD133+cells pre-treated with R2TNF as compared to untreated controls. We conclude that selective engagement of TNFR2 by TNF can drives RCCCD133+ proliferation and thereby increase sensitivity to cell cycle-dependent cytotoxicity.
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Affiliation(s)
- Rafia S Al-Lamki
- Department of Medicine, NIHR Cambridge Biomedical Research Centre, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Jun Wang
- Department of Medicine, NIHR Cambridge Biomedical Research Centre, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Jun Yang
- Department of Medicine, NIHR Cambridge Biomedical Research Centre, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Natalie Burrows
- School of Clinical Medicine, Cambridge Institute of Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK
| | - Patrick H Maxwell
- School of Clinical Medicine, Cambridge Institute of Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK
| | - Timothy Eisen
- Department of Oncology, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Anne Y Warren
- Department of Pathology, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK
| | - Sakari Vanharanta
- MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge CB2 0XZ, UK
| | - Simon Pacey
- Department of Oncology, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Peter Vandenabeele
- VIB Inflammation Research Center, Ghent University, UGhent-VIB Research Building FSVM, 9052 Ghent, Belgium
| | - Jordan S Pober
- Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520-8089, USA
| | - John R Bradley
- Department of Medicine, NIHR Cambridge Biomedical Research Centre, University of Cambridge, Cambridge CB2 0QQ, UK
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36
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Singh A, Srivastava AN, Akhtar S, Siddiqui MH, Singh P, Kumar V. Correlation of CD133 and Oct-4 expression with clinicopathological and demographic parameters in oral squamous cell carcinoma patients. Natl J Maxillofac Surg 2018; 9:8-13. [PMID: 29937653 PMCID: PMC5996651 DOI: 10.4103/njms.njms_60_17] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVE Squamous cell carcinoma of oral cavity is one of the most common cancers of Indian subcontinent with the 5-year survival rate of 50% despite the recent advances in the treatment. The aim of the present study was to study cancer stem cell markers CD133 and Oct-4 in oral squamous cell carcinoma (OSCC) patients and their correlation with clinicopathological variables. MATERIALS AND METHODS This was a prospective study which included 50 cases of histopathologically proven squamous cell carcinoma of oral cavity. Expression of CD133 and Oct-4 was evaluated by immunohistochemistry (IHC) and their expression was correlated with various clinicopathological and demographic parameters. RESULTS CD133 expression was seen in 20.6% cases of clinical Stage I-II and in 79.4% of clinical stage of III-IV OSCC patients, the difference being statistically significant with the P = 0.048. There was no statistically significant association between CD133 expression and any other clinicopathological or demographic variable. Oct-4 was expressed only in one case. CONCLUSIONS CD133 expression was significantly seen higher in Stage III-IV tumors, the stem cells may be responsible for the aggressiveness of the OSCCs and these stem cells can be potential prognostic markers and targets for the future targeted therapy.
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Affiliation(s)
- Alok Singh
- Department of Pathology, Era's Lucknow Medical College and Hospital, Lucknow, Uttar Pradesh, India
| | - Anand Narain Srivastava
- Department of Pathology, Era's Lucknow Medical College and Hospital, Lucknow, Uttar Pradesh, India
| | - Salman Akhtar
- Department of Bioengineering, Integral University, Lucknow, Uttar Pradesh, India
| | - Mohammad Haris Siddiqui
- Department of Pathology, Era's Lucknow Medical College and Hospital, Lucknow, Uttar Pradesh, India
| | - Pooja Singh
- Department of Pathology, Era's Lucknow Medical College and Hospital, Lucknow, Uttar Pradesh, India
| | - Vijay Kumar
- Department of Surgical Oncology, King George's Medical University, Lucknow, Uttar Pradesh, India
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37
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SOX2-silenced squamous cell carcinoma: a highly malignant form of esophageal cancer with SOX2 promoter hypermethylation. Mod Pathol 2018; 31:83-92. [PMID: 28862264 DOI: 10.1038/modpathol.2017.112] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Revised: 07/06/2017] [Accepted: 07/06/2017] [Indexed: 02/08/2023]
Abstract
This study originally aimed to investigate whether the overexpression of SOX2 is associated with the poor prognosis of patients with squamous cell carcinoma of the esophagus. However, we unexpectedly found that esophageal squamous cell carcinomas completely lacking SOX2 expression showed distinct pathologic features and highly aggressive clinical courses. The study cohort consisted of 113 consecutive patients with esophageal squamous cell carcinoma who underwent surgical resection without neoadjuvant therapy. Immunostaining on tissue microarrays and whole sections revealed that 8/113 (7%) cases were entirely negative for this transcriptional factor. SOX2-negative cancers were histologically less differentiated (P=0.002) and showed higher pT and pStages (P=0.003 and 0.007, respectively) than SOX2-positive cases. A remarkable finding was widespread lymphatic infiltration distant from the primary invasive focus, which was observed in 4 SOX2-negative cancers (50%), but none of the SOX2-positive cases. All separate dysplastic lesions observed in SOX2-negative cases were also SOX2-negative. The negative expression of SOX2 appeared to be an independent poor prognostic factor (OR=7.05, 95% CI=1.27-39.0). No mutations were identified in the coding or non-coding regions of SOX2. Fluorescent in situ hybridization did not show any copy-number variations in this gene. Since the SOX2 promoter contains an extensive CpG island, SOX2-negative cases underwent methylation-specific PCR, which disclosed promoter hypermethylation in all cases. In conclusion, SOX2-silenced squamous cell carcinomas of the esophagus appear to be a minor, but distinct form of malignancy characterized by extensive lymphatic invasion, a poor prognosis, and potential association with multiple SOX2-negative neoplastic lesions. The hypermethylation of the promoter region is seemingly a critical epigenetic event leading to SOX2 silencing.
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38
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Karbanová J, Lorico A, Bornhäuser M, Corbeil D, Fargeas CA. Prominin-1/CD133: Lipid Raft Association, Detergent Resistance, and Immunodetection. Stem Cells Transl Med 2017; 7:155-160. [PMID: 29271118 PMCID: PMC5788878 DOI: 10.1002/sctm.17-0223] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2017] [Accepted: 11/17/2017] [Indexed: 01/17/2023] Open
Abstract
The cell surface antigen prominin‐1 (alias CD133) has gained enormous interest in the past 2 decades and given rise to debates as to its utility as a biological stem and cancer stem cell marker. Important and yet often overlooked knowledge that is pertinent to its physiological function has been generated in other systems given its more general expression beyond primitive cells. This article briefly discusses the importance of particular biochemical features of CD133 with relation to its association with membrane microdomains (lipid rafts) and proper immunodetection. It also draws attention toward the adequate use of detergents and caveats that may apply to the interpretation of the results generated. Stem Cells Translational Medicine2018;7:155–160
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Affiliation(s)
- Jana Karbanová
- Tissue Engineering Laboratories, Biotechnology Center (BIOTEC), Dresden, Germany.,DFG Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Dresden, Germany
| | - Aurelio Lorico
- Department of Pathology, College of Medicine, Roseman University of Health Sciences, Las Vegas, Nevada, USA
| | - Martin Bornhäuser
- DFG Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Dresden, Germany.,Medical Clinic and Polyclinic I, University Hospital Carl Gustav Carus, Dresden, Germany
| | - Denis Corbeil
- Tissue Engineering Laboratories, Biotechnology Center (BIOTEC), Dresden, Germany.,DFG Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Dresden, Germany
| | - Christine A Fargeas
- Tissue Engineering Laboratories, Biotechnology Center (BIOTEC), Dresden, Germany
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39
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Saeednejad Zanjani L, Madjd Z, Abolhasani M, Andersson Y, Rasti A, Shariftabrizi A, Asgari M. Cytoplasmic expression of CD133 stemness marker is associated with tumor aggressiveness in clear cell renal cell carcinoma. Exp Mol Pathol 2017; 103:218-228. [PMID: 29050853 DOI: 10.1016/j.yexmp.2017.10.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2017] [Revised: 09/10/2017] [Accepted: 10/15/2017] [Indexed: 12/13/2022]
Abstract
Prominin-1 (CD133) is one of the most commonly used markers for cancer stem cells (CSCs), which are characterized by their ability for self-renewal and tumorigenicity. However, the clinical and prognostic significance of CSCs in renal cell carcinoma (RCC) remains unclear. The aim of this study was to investigate the expression patterns and prognostic significance of the cancer stem cell marker CD133 in different histological subtypes of RCC. CD133 expression was evaluated using immunohistochemistry in 193 well-defined renal tumor samples on tissue microarrays, including 136 (70.5%) clear cell renal cell carcinomas (CCRCCs), 26 (13.5%) papillary RCCs, and 31 (16.1%) chromophobe RCCs. The association between CD133 expression and clinicopathological features as well as the survival outcomes was determined. There was a statistically significant difference between CD133 expression among the different RCC subtypes. In CCRCC, higher cytoplasmic expression of CD133 was significantly associated with increase in grade, stage, microvascular invasion (MVI) and lymph node invasion (LNI), while no association was found with the membranous expression. Moreover, on multivariate analysis, TNM stage and nuclear grade were independent prognostic factors for overall survival (OS) in cytoplasmic expression. We showed that higher cytoplasmic CD133 expression was associated with more aggressive tumor behavior and more advanced disease in CCRCC but not in the other examined subtypes. Our results demonstrated that higher cytoplasmic CD133 expression is clinically significant in CCRCC and is associated with increased tumor aggressiveness and is useful for predicting cancer progression.
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Affiliation(s)
| | - Zahra Madjd
- Oncopathology Research Centre, Iran University of Medical Sciences (IUMS), Tehran, Iran; Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran.
| | - Maryam Abolhasani
- Oncopathology Research Centre, Iran University of Medical Sciences (IUMS), Tehran, Iran; Hasheminejad Kidney Center, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Yvonne Andersson
- Department of Tumor Biology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Arezoo Rasti
- Oncopathology Research Centre, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Ahmad Shariftabrizi
- Department of Nuclear Medicine and Molecular Imaging, State University of New York at Buffalo, Buffalo, NY 14223, USA
| | - Mojgan Asgari
- Oncopathology Research Centre, Iran University of Medical Sciences (IUMS), Tehran, Iran; Hasheminejad Kidney Center, Iran University of Medical Sciences (IUMS), Tehran, Iran.
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40
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DeSantis KA, Stabell AR, Spitzer DC, O'Keefe KJ, Nelson DA, Larsen M. RARα and RARγ reciprocally control K5 + progenitor cell expansion in developing salivary glands. Organogenesis 2017; 13:125-140. [PMID: 28933645 PMCID: PMC5669212 DOI: 10.1080/15476278.2017.1358336] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2017] [Revised: 05/25/2017] [Accepted: 07/15/2017] [Indexed: 12/15/2022] Open
Abstract
Understanding the mechanisms of controlled expansion and differentiation of basal progenitor cell populations during organogenesis is essential for developing targeted regenerative therapies. Since the cytokeratin 5-positive (K5+) basal epithelial cell population in the salivary gland is regulated by retinoic acid signaling, we interrogated how isoform-specific retinoic acid receptor (RAR) signaling impacts the K5+ cell population during salivary gland organogenesis to identify RAR isoform-specific mechanisms that could be exploited in future regenerative therapies. In this study, we utilized RAR isoform-specific inhibitors and agonists with murine submandibular salivary gland organ explants. We determined that RARα and RARγ have opposing effects on K5+ cell cycle progression and cell distribution. RARα negatively regulates K5+ cells in both whole organ explants and in isolated epithelial rudiments. In contrast, RARγ is necessary but not sufficient to positively maintain K5+ cells, as agonism of RARγ alone failed to significantly expand the population. Although retinoids are known to stimulate differentiation, K5 levels were not inversely correlated with differentiated ductal cytokeratins. Instead, RARα agonism and RARγ inhibition, corresponding with reduced K5, resulted in premature lumenization, as marked by prominin-1. With lineage tracing, we demonstrated that K5+ cells have the capacity to become prominin-1+ cells. We conclude that RARα and RARγ reciprocally control K5+ progenitor cells endogenously in the developing submandibular salivary epithelium, in a cell cycle-dependent manner, controlling lumenization independently of keratinizing differentiation. Based on these data, isoform-specific targeting RARα may be more effective than pan-RAR inhibitors for regenerative therapies that seek to expand the K5+ progenitor cell pool. SUMMARY STATEMENT RARα and RARγ reciprocally control K5+ progenitor cell proliferation and distribution in the developing submandibular salivary epithelium in a cell cycle-dependent manner while regulating lumenization independently of keratinizing differentiation.
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Affiliation(s)
- Kara A. DeSantis
- Graduate program in Molecular, Cellular, Developmental, and Neural Biology, University at Albany, SUNY, Albany, NY, USA
- Department of Biological Science, University at Albany, SUNY, Albany, NY, USA
| | - Adam R. Stabell
- Department of Biological Science, University at Albany, SUNY, Albany, NY, USA
| | - Danielle C. Spitzer
- Graduate program in Molecular, Cellular, Developmental, and Neural Biology, University at Albany, SUNY, Albany, NY, USA
- Department of Pathology & Laboratory Medicine and Department of Biology, Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Kevin J. O'Keefe
- Graduate program in Molecular, Cellular, Developmental, and Neural Biology, University at Albany, SUNY, Albany, NY, USA
- Department of Biological Science, University at Albany, SUNY, Albany, NY, USA
| | - Deirdre A. Nelson
- Department of Biological Science, University at Albany, SUNY, Albany, NY, USA
| | - Melinda Larsen
- Graduate program in Molecular, Cellular, Developmental, and Neural Biology, University at Albany, SUNY, Albany, NY, USA
- The RNA Institute, University at Albany, SUNY, Albany, NY, USA
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41
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Klapdor R, Wang S, Hacker U, Büning H, Morgan M, Dörk T, Hillemanns P, Schambach A. Improved Killing of Ovarian Cancer Stem Cells by Combining a Novel Chimeric Antigen Receptor-Based Immunotherapy and Chemotherapy. Hum Gene Ther 2017; 28:886-896. [PMID: 28836469 DOI: 10.1089/hum.2017.168] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Ovarian cancer represents the most lethal gynecological cancer. Although cytoreductive chemotherapy and surgery lead to complete macroscopic tumor removal, most of the patients in advanced stages suffer from recurrent disease and subsequently die. This may be explained by the activity of cancer stem cells (CSC), which are a subpopulation of cells with an elevated chemoresistance and an increased capacity for self-renewal and metastatic spread. Specifically targeting these cells by adoptive immunotherapy represents a promising strategy to reduce the risk for recurrent disease. This study selected the widely accepted CSC marker CD133 as a target for a chimeric antigen receptor (CAR)-based immunotherapeutic approach to treat ovarian cancer. A lentiviral vector was generated encoding a third-generation anti-CD133-CAR, and clinically used NK92 cells were transduced. These engineered natural killer (NK) cells showed specific killing against CD133-positive ovarian cancer cell lines and primary ovarian cancer cells cultured from sequential ascites harvests. Additionally, specific activation of these engineered NK cells was demonstrated via interferon-gamma secretion assays. To improve clinical efficacy of ovarian cancer treatment, the effect of the chemotherapeutic agent cisplatin was evaluated together with CAR-transduced NK cell treatment. It was demonstrated that NK cells remain cytotoxic and active under cisplatin treatment and, importantly, that sequential treatment with cisplatin followed by CAR-NK cells led to the strongest killing effect. The specific eradication of ovarian CSCs by anti-CD133-CAR expressing NK92 cells represents a promising strategy and, when confirmed in vivo, shall be the basis of future clinical studies with the aim to prevent recurrent disease.
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Affiliation(s)
- Rüdiger Klapdor
- 1 Department of Gynecology and Obstetrics, Hannover Medical School , Hannover, Germany .,2 Institute for Experimental Hematology, Hannover Medical School , Hannover, Germany .,3 Cluster of Excellence REBIRTH, Hannover Medical School , Hannover, Germany
| | - Shuo Wang
- 1 Department of Gynecology and Obstetrics, Hannover Medical School , Hannover, Germany .,2 Institute for Experimental Hematology, Hannover Medical School , Hannover, Germany
| | - Ulrich Hacker
- 2 Institute for Experimental Hematology, Hannover Medical School , Hannover, Germany .,4 University Cancer Center Leipzig (UCCL), University Hospital Leipzig , Leipzig, Germany
| | - Hildegard Büning
- 2 Institute for Experimental Hematology, Hannover Medical School , Hannover, Germany .,3 Cluster of Excellence REBIRTH, Hannover Medical School , Hannover, Germany
| | - Michael Morgan
- 2 Institute for Experimental Hematology, Hannover Medical School , Hannover, Germany .,3 Cluster of Excellence REBIRTH, Hannover Medical School , Hannover, Germany
| | - Thilo Dörk
- 1 Department of Gynecology and Obstetrics, Hannover Medical School , Hannover, Germany
| | - Peter Hillemanns
- 1 Department of Gynecology and Obstetrics, Hannover Medical School , Hannover, Germany
| | - Axel Schambach
- 2 Institute for Experimental Hematology, Hannover Medical School , Hannover, Germany .,3 Cluster of Excellence REBIRTH, Hannover Medical School , Hannover, Germany .,5 Division of Hematology/Oncology, Boston Children's Hospital , Harvard Medical School, Boston, Massachusetts
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42
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The lacrimal gland: development, wound repair and regeneration. Biotechnol Lett 2017; 39:939-949. [DOI: 10.1007/s10529-017-2326-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Accepted: 03/23/2017] [Indexed: 01/16/2023]
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43
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Bobinger T, May L, Lücking H, Kloska SP, Burkardt P, Spitzer P, Maler JM, Corbeil D, Huttner HB. CD133-Positive Membrane Particles in Cerebrospinal Fluid of Patients with Inflammatory and Degenerative Neurological Diseases. Front Cell Neurosci 2017; 11:77. [PMID: 28396625 PMCID: PMC5366322 DOI: 10.3389/fncel.2017.00077] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Accepted: 03/03/2017] [Indexed: 01/10/2023] Open
Abstract
Background: Analysis of cerebrospinal fluid (CSF) is a frequently used diagnostic tool in a variety of neurological diseases. Recent studies suggested that investigating membrane particles enriched with the stem cell marker CD133 may offer new avenues for studying neurological disease. In this study, we evaluated the amount of membrane particle-associated CD133 in human CSF in neuroinflammatory and degenerative diseases. Methods: We compared the amount of membrane particle-associated CD133 in CSF samples collected from 45 patients with normal pressure hydrocephalus, parkinsonism, dementia, and cognitive impairment, chronic inflammatory diseases and 10 healthy adult individuals as controls. After ultracentrifugation of CSF, gel electrophoresis and immunoblotting using anti-CD133 monoclonal antibody 80B258 were performed. Antigen-antibody complexes were detected using chemiluminescence. Results: The amount of membrane particle-associated CD133 was significantly increased in patients with normal pressure hydrocephalus (p < 0.001), parkinsonism (p = 0.011) as well as in patients with chronic inflammatory disease (p = 0.008). Analysis of CSF of patients with dementia and cognitive impairment revealed no significant change compared with healthy individuals. Furthermore, subgroup analysis of patients with chronic inflammatory diseases demonstrated significantly elevated levels in individuals with relapsing-remitting multiple sclerosis (p = 0.023) and secondary progressive multiple sclerosis (SPMS; p = 0.010). Conclusion: Collectively, our study revealed elevated levels of membrane particle-associated CD133 in patients with normal pressure hydrocephalus, parkinsonism as well as relapsing-remitting and SPMS. Membrane glycoprotein CD133 may be of clinical value for several neurological diseases.
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Affiliation(s)
- Tobias Bobinger
- Department of Neurology, University Hospital Erlangen Erlangen, Germany
| | - Lisa May
- Department of Neurology, University Hospital Erlangen Erlangen, Germany
| | - Hannes Lücking
- Department of Neuroradiology, University Hospital Erlangen Erlangen, Germany
| | - Stephan P Kloska
- Department of Neuroradiology, University Hospital Erlangen Erlangen, Germany
| | - Petra Burkardt
- Department of Neurology, University Hospital Erlangen Erlangen, Germany
| | - Philipp Spitzer
- Department of Psychiatry, University Hospital Erlangen Erlangen, Germany
| | - Juan M Maler
- Department of Psychiatry, University Hospital Erlangen Erlangen, Germany
| | - Denis Corbeil
- Biotechnology Center, Technische Universität Dresden Dresden, Germany
| | - Hagen B Huttner
- Department of Neurology, University Hospital Erlangen Erlangen, Germany
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44
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CD133 expression in well-differentiated pancreatic neuroendocrine tumors: a potential predictor of progressive clinical courses. Hum Pathol 2016; 61:148-157. [PMID: 27864124 DOI: 10.1016/j.humpath.2016.10.022] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Revised: 10/18/2016] [Accepted: 10/28/2016] [Indexed: 01/11/2023]
Abstract
The present study aimed to elucidate whether the stemness molecule, CD133, is expressed in well-differentiated pancreatic neuroendocrine tumors (PanNETs; World Health Organization grades 1 and 2) and establish its clinical relevance using 2 separate cohorts. In the first series (n = 178) in which tissue microarrays were available, immunohistochemistry revealed that CD133 was expressed in 14 cases (8%). CD133+ PanNETs had higher TNM stages (P < .01), more frequent lymphovascular invasion (P = .01), and higher recurrence rates (P = .01). In the second cohort (n = 56), the expression of CD133 and CK19 was examined in whole tissue sections. CD133 and CK19 were positive in 10 (18%) and 36 (64%) cases, respectively. CD133 expression correlated with higher pT scores (P < .01), the presence of microscopic venous infiltration (P = .03), and shorter disease-free periods (P < .01). When cases were divided into grade 1 and 2 neoplasms, patients with CD133+ PanNET continued to have shorter disease-free periods than did those with CD133- tumors in both groups (P < .01 and P = .02, respectively). Although CK19+ cases had shorter disease-free periods than did CK19- cases in the whole cohort (P = .02), this difference was less apparent in subanalyses of grade 1 and 2 cases. CD133 expression also appeared to be an independent predictive factor for tumor recurrence in a multivariate analysis (P = .018). The CD133 phenotype was identical between primary and metastatic foci in 17 of 18 cases from which tissues of metastatic deposits were available. In conclusion, the combination of CD133 phenotyping and World Health Organization grading may assist in stratifying patients in terms of the risk of progressive clinical courses.
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45
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Thamm K, Graupner S, Werner C, Huttner WB, Corbeil D. Monoclonal Antibodies 13A4 and AC133 Do Not Recognize the Canine Ortholog of Mouse and Human Stem Cell Antigen Prominin-1 (CD133). PLoS One 2016; 11:e0164079. [PMID: 27701459 PMCID: PMC5049760 DOI: 10.1371/journal.pone.0164079] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Accepted: 09/19/2016] [Indexed: 02/07/2023] Open
Abstract
The pentaspan membrane glycoprotein prominin-1 (CD133) is widely used in medicine as a cell surface marker of stem and cancer stem cells. It has opened new avenues in stem cell-based regenerative therapy and oncology. This molecule is largely used with human samples or the mouse model, and consequently most biological tools including antibodies are directed against human and murine prominin-1. Although the general structure of prominin-1 including its membrane topology is conserved throughout the animal kingdom, its primary sequence is poorly conserved. Thus, it is unclear if anti-human and -mouse prominin-1 antibodies cross-react with their orthologs in other species, especially dog. Answering this issue is imperative in light of the growing number of studies using canine prominin-1 as an antigenic marker. Here, we address this issue by cloning the canine prominin-1 and use its overexpression as a green fluorescent protein fusion protein in Madin-Darby canine kidney cells to determine its immunoreactivity with antibodies against human or mouse prominin-1. We used immunocytochemistry, flow cytometry and immunoblotting techniques and surprisingly found no cross-species immunoreactivity. These results raise some caution in data interpretation when anti-prominin-1 antibodies are used in interspecies studies.
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Affiliation(s)
- Kristina Thamm
- Tissue Engineering Laboratories, Biotechnology Center (BIOTEC), Technische Universität Dresden, Dresden, Germany
| | - Sylvi Graupner
- Tissue Engineering Laboratories, Biotechnology Center (BIOTEC), Technische Universität Dresden, Dresden, Germany
| | - Carsten Werner
- DFG-Research Center and Cluster of Excellence for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Dresden, Germany
- Institute for Biofunctional Polymer Materials, Leibniz Institute of Polymer Research Dresden, Dresden, Germany
| | - Wieland B. Huttner
- Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
| | - Denis Corbeil
- Tissue Engineering Laboratories, Biotechnology Center (BIOTEC), Technische Universität Dresden, Dresden, Germany
- DFG-Research Center and Cluster of Excellence for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Dresden, Germany
- * E-mail:
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46
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CD133, Selectively Targeting the Root of Cancer. Toxins (Basel) 2016; 8:toxins8060165. [PMID: 27240402 PMCID: PMC4926132 DOI: 10.3390/toxins8060165] [Citation(s) in RCA: 72] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Revised: 05/08/2016] [Accepted: 05/10/2016] [Indexed: 12/20/2022] Open
Abstract
Cancer stem cells (CSC) are capable of promoting tumor initiation and self-renewal, two important hallmarks of carcinoma formation. This population comprises a small percentage of the tumor mass and is highly resistant to chemotherapy, causing the most difficult problem in the field of cancer research, drug refractory relapse. Many CSC markers have been reported. One of the most promising and perhaps least ubiquitous is CD133, a membrane-bound pentaspan glycoprotein that is frequently expressed on CSC. There is evidence that directly targeting CD133 with biological drugs might be the most effective way to eliminate CSC. We have investigated two entirely unrelated, but highly effective approaches for selectively targeting CD133. The first involves using a special anti-CD133 single chain variable fragment (scFv) to deliver a catalytic toxin. The second utilizes this same scFv to deliver components of the immune system. In this review, we discuss the development and current status of these CD133 associated biological agents. Together, they show exceptional promise by specific and efficient CSC elimination.
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Gurudev N, Florek M, Corbeil D, Knust E. Prominent role of prominin in the retina. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 777:55-71. [PMID: 23161075 DOI: 10.1007/978-1-4614-5894-4_4] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/11/2023]
Abstract
Prominin molecules represent a new family of pentaspan membrane glycoproteins expressed throughout the animal kingdom. The name originates from its localization on membrane protrusion, such as microvilli, filopodia, lamellipodia, and microspikes. Following the original description in mouse and human, representative prominin members were found in fish (e.g., Danio rerio), amphibian (Ambystoma mexicanum, Xenopus laevis), worm (Caenorhabditis elegans), and flies (Drosophila melanogaster). Mammalian prominin-1 was identified as a marker of somatic and cancer stem cells and plays an essential role in the visual system, which contributed to increased interest of the medical field in this molecule. Here we summarize recent data from various fields, including Drosophila, which will aid to our understanding of its still elusive function.
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Affiliation(s)
- Nagananda Gurudev
- Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstr. 108, 01307, Dresden, Germany
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48
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Wei X, Orjalo AV, Xin L. CD133 does not enrich for the stem cell activity in vivo in adult mouse prostates. Stem Cell Res 2016; 16:597-606. [PMID: 27010655 DOI: 10.1016/j.scr.2016.03.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Revised: 02/12/2016] [Accepted: 03/10/2016] [Indexed: 11/30/2022] Open
Abstract
CD133 is widely used as a marker for stem/progenitor cells in many organ systems. Previous studies using in vitro stem cell assays have suggested that the CD133-expressing prostate basal cells may serve as the putative prostate stem cells. However, the precise localization of the CD133-expressing cells and their contributions to adult murine prostate homeostasis in vivo remain undetermined. We show that loss of function of CD133 does not impair murine prostate morphogenesis, homeostasis and regeneration, implying a dispensable role for CD133 in prostate stem cell function. Using a CD133-CreER(T2) model in conjunction with a fluorescent report line, we show that CD133 is not only expressed in a fraction of prostate basal cells, but also in some luminal cells and stromal cells. CD133(+) basal cells possess higher in vitro sphere-forming activities than CD133(-) basal cells. However, the in vivo lineage tracing study reveals that the two cell populations possess the same regenerative capacity and contribute equally to the maintenance of the basal cell lineage. Similarly, CD133(+) and CD133(-) luminal cells are functionally equivalent in maintaining the luminal cell lineage. Collectively, our study demonstrates that CD133 does not enrich for the stem cell activity in vivo in adult murine prostate. This study does not contradict previous reports showing CD133(+) cells as prostate stem cells in vitro. Instead, it highlights a substantial impact of biological contexts on cellular behaviors.
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Affiliation(s)
- Xing Wei
- Department of Molecular and Cellular Biology, Baylor College of Medicine, United States; Graduate Program in Integrative Molecular and Biomedical Sciences, Baylor College of Medicine, United States
| | - Arturo V Orjalo
- Biological Technologies, Analytical Development & Quality Control, Genentech Inc., United States
| | - Li Xin
- Department of Molecular and Cellular Biology, Baylor College of Medicine, United States; Department of Pathology and Immunology, United States; Dan L. Duncan Cancer Center, Baylor College of Medicine, United States.
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49
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Fargeas CA, Corbeil D. Comments on the "Prognostic Impact and Clinicopathological Correlation of CD133 and ALDH1 Expression in Invasive Breast Cancer" and the "Commentary by Antonio Ieni and Giovanni Tuccari". J Breast Cancer 2016; 19:336-338. [PMID: 27721886 PMCID: PMC5053321 DOI: 10.4048/jbc.2016.19.3.336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Accepted: 06/27/2016] [Indexed: 11/30/2022] Open
Affiliation(s)
- Christine A. Fargeas
- Tissue Engineering Laboratories (BIOTEC), Technische Universität Dresden, Dresden, Germany
| | - Denis Corbeil
- Tissue Engineering Laboratories (BIOTEC), Technische Universität Dresden, Dresden, Germany
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50
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Reichert D, Friedrichs J, Ritter S, Käubler T, Werner C, Bornhäuser M, Corbeil D. Phenotypic, Morphological and Adhesive Differences of Human Hematopoietic Progenitor Cells Cultured on Murine versus Human Mesenchymal Stromal Cells. Sci Rep 2015; 5:15680. [PMID: 26498381 PMCID: PMC4620509 DOI: 10.1038/srep15680] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2015] [Accepted: 10/01/2015] [Indexed: 02/07/2023] Open
Abstract
Xenogenic transplantation models have been developed to study human hematopoiesis in immunocompromised murine recipients. They still have limitations and therefore it is important to delineate all players within the bone marrow that could account for species-specific differences. Here, we evaluated the proliferative capacity, morphological and physical characteristics of human CD34+ hematopoietic stem and progenitor cells (HSPCs) after co-culture on murine or human bone marrow-derived mesenchymal stromal cells (MSCs). After seven days, human CD34+CD133– HSPCs expanded to similar extents on both feeder layers while cellular subsets comprising primitive CD34+CD133+ and CD133+CD34– phenotypes are reduced fivefold on murine MSCs. The number of migrating HSPCs was also reduced on murine cells suggesting that MSC adhesion influences cellular polarization of HSPC. We used atomic force microscopy-based single-cell force spectroscopy to quantify their adhesive interactions. We found threefold higher detachment forces of human HSPCs from murine MSCs compared to human ones. This difference is related to the N-cadherin expression level on murine MSCs since its knockdown abolished their differential adhesion properties with human HSPCs. Our observations highlight phenotypic, morphological and adhesive differences of human HSPCs when cultured on murine or human MSCs, which raise some caution in data interpretation when xenogenic transplantation models are used.
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Affiliation(s)
- Doreen Reichert
- Tissue Engineering Laboratories (BIOTEC), Technische Universität Dresden, 01307 Dresden, Germany
| | - Jens Friedrichs
- Institute for Biofunctional Polymer Materials, Leibniz Institute of Polymer Research Dresden, 01069 Dresden, Germany
| | - Steffi Ritter
- Tissue Engineering Laboratories (BIOTEC), Technische Universität Dresden, 01307 Dresden, Germany
| | - Theresa Käubler
- Tissue Engineering Laboratories (BIOTEC), Technische Universität Dresden, 01307 Dresden, Germany
| | - Carsten Werner
- Institute for Biofunctional Polymer Materials, Leibniz Institute of Polymer Research Dresden, 01069 Dresden, Germany.,DFG Research Center and Cluster of Excellence for Regenerative Therapies Dresden 01307 Dresden, Germany
| | - Martin Bornhäuser
- Medical Clinic and Polyclinic I, University Hospital Carl Gustav Carus, 01307 Dresden, Germany.,DFG Research Center and Cluster of Excellence for Regenerative Therapies Dresden 01307 Dresden, Germany
| | - Denis Corbeil
- Tissue Engineering Laboratories (BIOTEC), Technische Universität Dresden, 01307 Dresden, Germany.,DFG Research Center and Cluster of Excellence for Regenerative Therapies Dresden 01307 Dresden, Germany
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